Oncology Flashcards
What are 3 caregories tissues can be divided in based on cell division rates?
Give examples of each
1) Labile (continuously dividing)
- Surface epithelium (skin, mucosa, ducts)
- Cells of the bone marrow
2) Stable (quiescent - divide in reponse to stimuli)
- parenchymal cells of the liver, kidney and pancreas
- mesenchymal cells - fibroblasts, endothelial, smooth mucle cell, leukocytes
3) permanent (non dividing)
- cardiomyocytes, neurons and skeletal muscle
What are the key cell cycle check points?
What do these check?
- G2/M checkpoint -> check for damaged or unduplicated DNA
- Restriction point -> centrosome duplication, growth in mass
- G1/S checkpoint -> check for DNA damage
What are the 5 phases of the cell cycle?
Buzzwords for each one
G0; phase of stable cells
G1; presynaptic growth
S; DNA synthesis
G2 Premitotic growth
M; Mitosis
what are key regulators of the cell cycle
- cyclins
- check points (G2/M, Restriction point G1/s)
- growth factors
- integrins
What are CDKs ?
Why are these important?
Cyclin dependent kinases;
- key regulartors of the cell cycle
- Expressed constitutively and phosphorylate target proteins
- Anticancer therapeutic targets (Verzenio, Kisqali, and Ibrance are CDK4/6 inhibitors approved for hormone receptor-positive, HER2- negative metastatic breast cancer
what are cyclins ?
– Activate CDKs
– Cell cycling requires the alternate formation and degradation of cyclin/CDK complexes
What are CDKIs?
what are the two main groups of CDKIs (inhibitors)?
- CDKIs are tumor suppressors, but overexpression is linked to cellular senescence
- CDKN1s: p21, p27, p57
- CDKN2s: INK4: p16, p15, p18, p19
2 essential growth inhibitors ?
- p58
- TGF-ß
How to growth inhibitors affect ribosome function
Growth inhibitos (eg TGFß, p53) -> stimulate CDK inhibitors (e.g. p16)-> inactivate cyclins -> inactivated cyclins cannot hyperphosphorylate the ribosome, preventing binding to the binding site on the genome.
what is the incidence of p53 defects in human cancers and what are these defects responsible for?
p53 is defective in >50% of human cancers
- demaged DNA is not detected and repaired
- decreased or defective. apoptosis -> uncontrolled cell growth
what are the key steps in signaling mechanisms of cell growth ?
Growth factor/integrins -> signal transduction -> transcription of genes that were silent (differentiation, migration, ECM production, angiogenesis) -> entry of the cell into the cell cycle -> proliferation
What are the key signaling pathways?
- receptors with intrinsic Tyrosine kinase activity (bind growth factor) -> activate PI3 kinase pathway or MAP-kinase pathway or IP3 pathway ->multiple effects
- Gprotein coupled receptors -> bind signaling molecules -> cAMP pathways -> multiple effects
- Receptors withot intrinsic tyrosine kinase activity -> JAK/STAT pathway `
Why are the PI3K, AKT and mTOR pathways important?
Mutations in the PI3K, AKT, mTOR pathways are almost obligatory steps for neoplastic transformation
what is the role of the AKT pathway;
- The AKT pathways are central to maintain energy balance
- Signaling through AKT is important for glucose and fat metabolism
- AKT pathways are also critical for cell survival
what are the classic hallmarks of cancer?
- self sufficiency in cell growth signals
- insensitivity to anti-growth signals
- tissue invasion and metastasis
- limitless replicative potential
- sustained angiogenesis (gain access to vascualture)
- evading apoptosis
what are key basis of cancer that allow for metastasis?
- Induce or access the vasculature
- Resist cell death
what are the enabling and emerging hallmarks of cancer
enabling;
- tumour-promoting inflammation
- genome instability and mutation -> non-mutation epigenetic reprogramming
Emerging
- deregulating cellular energetics
- avoid immune destruction
- unlocking phenotypic plasticity (differentiation)
Cancer emerges when_____
?
Phenotipic plasticity occurs and senescent cells are sustained and induced in the microenvironement
what are proto-oncogenes?
growth promoting genes that promote autonomous cell growth and self sufficiency
what are oncoproteins ?
proteins that lack internal regulatory elements
what do oncogenes produce?
- Growth Factors * PDGF, TGF, FGF
- Growth Factor Receptors * Tyrosine kinase receptor, PDGFR
- Signal transducing proteins * GTP binding proteins (Ras), non-receptor TK
- Nuclear regulatory proteins (transcription factors)
- C-Myc, N-Myc, Jun, Fos
- Cell cycle regulators/Control proteins
- Cyclins, cyclin-dependent kinase
- CDK-inhibitors, checkpoint components
Draw a diagram describing ongogene activation.
are oncogene mutations dominant, recessive or heterozygous?
dominant
what is a key dowstream oncogenic effect of mutations in C-Ras/kit?
dominant activators or uncontrolled cell growth
What are tumour supressor genes?
Antigrowth genes -> keep cells in a senecent state
Loss/inactivation of TSGs can result in cellular
transformation and give rise to cancer
Give examples of tumour supressor genes?
are mutations recessive or heterozygous in these
Retinoblastoma susceptibility (RB1), p53 (TP53) and PTEN genes
Mutations are dominant recessive
What are the main modes of inactivation of tumour supressor genes?
– Genetic mechanisms
* Loss of heterozygosity
* Deletion
* Point mutations
– Epigenetic mechanisms (Gene silencing)
* Promoter methylation
What gene sequence activation is critical in the formation of osteosarcoma?
PI3K/AKT pathway activation due to PTEN deletion;
- In dogs, this occurs through HOMOZYGOUS DELETION (both copies of the PTEN gene) about 30-40% of the time
- In humans, this occurs through METHYLATION of a CpG island required for the induction of PTEN more than 80% of the time
what is more common, activation of proto-ongogenes or deletion of tumour supressor genes?
Loss of TSGs seems to occur more frequently than activation of proto-oncogenes
what are microscopic charachteristics of normal vascularture and neoplastic angiogenesis
Normal
- clear division of arterioles -> capilallaries -> venuoles
- Regular shapes
- organised
Abnormal
* Tortuous
* Irregularly shaped
* Unstable and leaky
* Disorganized
what effect does inhibiting angiogenesis have on tumour growth ?
*Inhibition of angiogenesis alone does not have a substantive impact to prevent, delay, or reverse tumor progression
* Inhibition of angiogenesis can result in blood vessel normalization, or restoration of the normal phenotype of blood vessel cells and patterns of circulation
what is the clinical relevance of angiogenesis ?
- Maintain a suitable oxygen environment and provide
access to nutrients - Evade apoptosis, necrosis, necroptosis, ferroptosis, and autophagy
- Microvessel density often shows a positive correlation with biological behavior
Despite targeting angiogenesis does not prevent tumour growth, why do we still target these clinically ?
Give an example of a drug that does this in animals ?
Blood vessel normalization can improve systemic drug delivery
- The only drug approved for companion animals that has a potential (small) antiangiogenic effect is toceranib
Is metastasis a direct extension of the primary tumour ?
Not a direct extension of the primary tumor (distinct from
invasion)
what is te stepwise process in metastasis ?
- Detach from primary mass (motility)
- Invade basement membrane (MMPs)
- Intravasation
- Survive in circulation (avoid anoikis, evade immune surveillance, resist physical stress)
- Arrest in circulation (marginate and adhere to vessel or lodge in capillary bed)
- Extravasation
- Invade basement membrane (MMPs)
- Create new tumor mass (survive, proliferate, grow, promote angiogenesis)
- Repeat (metastasis form metastasis)
what are the main pathways of spread for neoplasia which is metastasising ?
*Direct seeding of body cavities and surfaces
* Lymphatic spread
* Hematogenous spread
* bronchogenic
What is the seeding of a body cavity and surface?
where is it most common?
- Occurs whenever malignant neoplasm penetrates into the body cavity
- Peritoneal cavity is most commonly involved
- Other cavities:
– Pleural, pericardial
– Subarachnoid, joint spaces - It is a characteristic of carcinomas resulting in a condition called “carcinomatosis”
– Pancreatic exocrine adenocarcinoma – Ovarian carcinoma
what is carcinomatosis ?
in which tumours is this most commonly seen
Seeding of carcinomas into a body cavity or surface
– Pancreatic exocrine adenocarcinoma
– Ovarian carcinoma
what pathway do carcinomas most commonly metastasise via?
lymphatics
what is haematogenous metastasis
- Direct blood vessel invasion
- Indirect route via lymphatic system
- Carcinomas and sarcomas
- Lung – 1st capillary bed after vena cava
- Liver – 1st capillary bed after portal vein
- Arterial metastasis occurs less frequently in the liver because of
their thick muscular walls * Bone metastases
what is the Warburg effect?
It is the reliance of cancer cells on aerobic glycolysis.
Normal cells rely on mitochondrial oxidative phosphorylation to generate energy (ATP) - it is unclear why cancer uses this ineficient aerobic gycolisis pathway
how can cancers glucose metabolism be used to determine if there is a response to therapy ?
Response to therapy is predicted by the ability to disrupt glucose metabolism as measured by FDG-PET
-> ie Anticancer therapies decrease the glucose metabolism by tumours
what is meant by genome instability in cancer formation ?
- Tumors disable DNA replication and mitosis checkpoints
- Rapid cell division prevents efficient and appropriate repair of DNA damage or replication-induced mutations
- DNA damage repair machinery is in hyperdrive, creating poorly repaired and chaotic genomes
- Instability begets instability
Is one tumour supressor gene enough to cause a tumour?
No, multiple are needed
what is the big bang model ?
- Initial spectrum of mutations determines biological behavior
- Later mutations do not provide an advantage to gain a foothold in the presence of a highly heterogeneous cell population
How many mutations does it take to form a tumour ?
in vitro suggests 2. Usually, 5-10 are needed to estimate cancer traits
What is the risk profile associated with mammary cancer and spey timeline in dogs
Dogs spayed before their first estrous cycle have a greatly reduced risk of developing breast cancer, with the risk rising to 26% for dogs that are spayed after their second estrus
what age is mammery cancer most commonly seen in dogs?
Mammary tumors pri- marily affect late middle-aged (9 to 11 years) female intact dogs, with an increased incidence beginning at approximately 6 years of age.6
Why does the risk of mammary cancer increase the longer the dog remains unspayed ?
Sexual steroid hormones likely have their primary effect on target cells during the very early stages of mammary carcinogenesis in dogs; thus, the protective effect of spaying is lost with time. In addition to the influence of ovarian hormones on breast cancer development, the use of medroxyprogesterone acetate (progestin and estrogen combination) products to prevent estrus or to treat pseudopregnancy has been linked to an increased incidence of mammary tumor development in dogs
is prostatic cancer at higher risk in intact dogs?
No, prostatic hyperplasia is, and in man prostatic neoplasia is. To the contrary, neutered dogs have been shown to be at increased risk. Castration is likely not an initiating event, but is thought to favor tumor progression.
What are histiologic features of hyperplasia vs benign neoplasia vs malignant neoplasia?
What is the nomenclature of common tumour types in both their benign and malignant forms?
What are the molecular features underlying the grading criteria?
what are the grades and features of importance in mast cell tumours, for cat and dog, and lymphoma?
what are the grades and features of importance in squamous cell carcinoma, haemangiosarcoma, soft tissue sarcoma ?
Squamous; grade 1->3. features of improtance are Overall differentiation, mitotic index, nuclear
pleomorphism, invasion, stromal reaction
Hemangiosarcoma; grade 1->3. Overall differentiation, nuclear pleomorphism,
mitotic index, necrosis
Soft tissue sarcoma (dog); grade 1, 2, 3 or mitotic index >9,* mitotic index <9*. Overall differentiation, mitotic index, necrosis
Fill in the following table for diagnostic, immunohistochemical markers/panels and respective turmour types in dogs and cats
what are risk factors associated with mammary carcinoma? and breeds most at risk
Obesity, high dietary fat intake, late age at spay, and some breeds
(e.g., English Springer spaniel, Pointer, Poodle, Boston terrier, Dachshund, German shepherd, Chihuahua)
what are risk factors associated with osteosarcoma? and breeds most at risk
High weight, high height, early castration/spay, some breeds (e.g., Irish wolfhound, Saint Bernard, Great Dane, Rottweiler, Irish setter, Doberman Pinscher, golden retriever, Labrador retriever, Leonberger)
What are the risk factors associated with transitional cell carcinoma? and breeds most at risk
Being neutered, exposure to phenoxy-acid containing herbicides, frequent flea dipping, some breeds (e.g., Scottish terrier, Beagle, Shetland sheepdog, Wirehaired fox terrier, West Highland white terrier)
breeds over represented for mast cell turmour
Some breeds (e.g., Boxer, Rhodesian ridgeback, Vizsla, Boston terrier, Weimaraner, Chinese Shar-Pei, Bullmastiff, Dutch pug, Labrador retriever, American Staffordshire terrier, golden retriever, English setter, English pointer)
What are the risk factors associated with transitional cell carcinoma? and breeds most at risk
ETS, exposure to chemicals containing 2,4-dichlorophenoxyacetic acid, some breeds (e.g., Bullmastiff, Boxer, Scottish terrier, Gordon setter, Irish wolfhound, Basset hound, golden retriever)
what are risk factors for feline lymphoma
FeLV, FIV, environmental tobacco smoke
what are risk factors for feline sarcoma
Vaccine injection
what are risk factors for feline cutaneous squamous cell carcinoma
Solar irradiation
define paraneoplastic syndrome;
Paraneoplastic syndromes (PNSs) are neoplasm-associated alter- ations in bodily structure and/or function that occur distant to the tumor.
what is cancer cahexia and cancer anorexia?
The weight loss and metabolic alterations observed in cancer patients despite adequate nutritional intake are termed cancer cachexia, whereas alterations observed as the result of poor nutritional intake are termed cancer anorexia.
in human medicine, what proportion of deaths is associated with cancer cahexia and why?
approximately 20% of cancer deaths
patients with cancer cachexia can have significantly reduced survival times, and many patients are unable to undergo appropriate therapy because of their poor clinical status.
what treatment may offer a solution to cancer cahexia in dogs
A plasmid-DNA–mediated approach utilizing growth hormone–releasing hormone (GHRH) in dogs appears to increase insulin-like growth factor-1 (IGF-1) levels (a measure of GHRH activity) and may represent a mecha- nism for attenuating cancer cachexia
what are the causes of hypoproteinemia in cancer patients?
impaired synthesis and/or increased loss into the GI tract or urine
- PLE is thought to result from an increase in mucosal serum protein per- meability because of mucosal erosion, ulceration, or lymphatic obstruction.
How do you treat PLE from paraneoplastic syndrome ?
The treatment for PLE consists of treating the primary malignancy; however, those patients with a lymphangiectasia-related PLE may also be treated with medium-chain triglycerides that do not undergo trans- port by intestinal lymphatics.
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what is the most common form of paraneoplastic syndrome in dogs. How do these occur?
gastroduodenal ulceration is mast cell tumor (MCT).
excess histamine seen in MCTs stimulates gastric H2 receptors, leading to increased gastric acid secretion. Clinical manifestations of mucosal damage and/or ulceration with gastric vessel thrombosis occur in association with gastric hyperacidity. Plasma histamine concentrations are elevated in approximately 75% of dogs with macroscopic MCT, although only 30% have GI signs
What is the most common pareneoplastic syndrome in dogs and what is the treatment of this?
Gastroduodenal ulceration in mast cell tuomorst due to histamine stimulating H2 cells to produce acid.
Symptomatic therapies such as proton- pump inhibitors, H2 blockers, misoprostol, sucralfate, and rehydra- tion may be helpful in combating PNS-associated gastroduodenal ulceration.
in addition to mast cells, what tumour has been associated with gastroduodenal ulceration ?
gastrinoma (gastrin-secreting non–islet cell pancreatic tumor).
what are the most common cancers that cause hypercalcaemia in dogs?
Most common are;
Lymphoma (10-35%)
Anal sac apocrine gland adenocarcinoma (25%)
Multiple myeloma (20%
Parathyroid tumors
Renal angiomyxoma
Mammary tumors
Thymoma
How often is hypercalcaemia associated with cancer in dogs and cats?
two-thirds of dogs and one-third of cats with hypercalcemia.
what is by far the most common cancer that causes hypercalcaemia of malignancy ? what is the incidence
Lymphoma is the most common cause of HM (10% to 35% occurrence)
what are the cellular and molecular mechanisms that cuase hypercalcaemia of malignancy?
The causes of HM are varied and include;
- ectopic production of parathormone (PTH)
- PTH-related peptide (PTH-rp) by the tumor
- extensive and usually multifocal lyticbone metastases,
- primary hyperparathyroidism,
- tumor-associated prostaglandins (PGE1/2),
- interleukin-1-β (IL-1β, previously known as osteoclast-activating factor [OAF]),
- transforming growth factor-β (TGF-β), and receptor activator of nuclear factor kappa-B ligand (RANKL).
which form of TGF-ß is involved in hypercalcaemia of malignancy and how does this do that?
in which tumours does this occur?
TGF-β1 regulates the mRNA stability of PTH-rp. HM seen in lymphoma and anal sac apocrine gland adenocarcinoma is commonly caused by tumor- associated PTH-rp.
what is PTH-rp ?
16-kDa protein with significant sequence identity to PTH, suggesting it may act and function like PTH. This is upregulated by TGF-ß1 which is commonly secreted in lymphoma and AGASACA
what are differentials for hypercalcaemia of malignancy from neoplasia?
hypercalcemia differential diagno- ses include “lab error” (lipemia and hemolysis), acute renal failure, hypervitaminosis D, hypoadrenocorticism, and granulomatous disease.
If you are concerned that your hypercalcaemia is secondary to lipemia and not of malignancy, how should you interpret this result?
Ionized calcium. Otherwise interpret the calcium value in relation to the level of serum albumin if ionized calcium determination is not available.
Adjustedcalcium(mg/dL)=
[Calcium (mg / dL) − albumin (g / dL)] + 3.5
what may cause an increase in clinical signs of hypercalcaemia in a patient HM ?
Acidotic HM patients may have an increase in clinical signs of hypercalcemia when compared to nonacidotic HM patients.
which levels of calcium are classified as a medical emergency?
calcium > 18 mg/dL
what are the primary clincal manifestations of hypercalcaemia of malignancy and why?
primary clinical manifestations of HM are due to renal function impairment.
An inability to concentrate urine is the initial manifestation of hypercalcemia and is due to decreased responsiveness to antidiuretic hormone (ADH) at the distal tubule; the calcium then decreases renal blood flow and glomerular filtra- tion rate (GFR) as the result of severe vasoconstriction. Calcium salt deposition in the renal parenchyma may also contribute to renal azotemia, although this is uncommon. The urinary epithe- lium may then undergo degeneration, and in severe cases, necrosis results in exposure of the basement membrane of the renal tubule. The situation worsens as the patient becomes polyuric and polydip- sic, resulting in progressive dehydration. I
what are sequela of hypercalcaemia of malignancy?
Renal function impairment
constipation, hypertension, twitching, weakness, shaking, depression, vomiting, bradycardia, stupor, and possibly coma and/or death.
How do you approach the treatment of a patient with hypercalcaemia of malignancy ?
Find the cause (stage for lymphoma, rectal for agasaca ) and see table
what would you expect to see on parathyroid testing of a dog or cat with hypercalcaemia of malignancy?
Typically have low PTH and high PTH-rp concentrations; however, the cause of the HM can usually be delineated with appropriate diagnostics before the return of PTH/PTH-rp assay results, and such tests may not be routinely needed.
why is it important to try and identify the cuase of the hypercalcaemia of malignancy before starting treatment ?
The premature administration of symptomatic therapy that includes the use of corticosteroids can mask the neoplasia.
f lymphoma is the under- lying cause of the HM, the use of corticosteroids may interfere with the ability to confirm a diagnosis, necessitating either additional diagnostics and/or waiting to determine if the lymphoma reappears after glucocorticoid withdrawal. In addition, glucocorticoids may induce resistance to other chemotherapy agents with a decrease in the ability to induce a complete remission, as well as a decrease in the length of survival.
why is 0.9% saline given in the treatment of hypercalcaemia of malignancy?
And why is furosemide used?
management of existing dehydration and to expand the extracellular fluid volume, increase GFR, increase calciuresis and natriure- sis, and decrease calcium reabsorption by the kidneys. Once rehydrated, the loop diuretic furosemide with continued normosa- line diuresis can be utilized to potently inhibit calcium reabsorption in the ascending loop of Henle
why are corticosteorids effective at reducing calcium leves in hypercalcaemia of malignancy?
Why must these not be given immediatelly after the diagnosis of hypercalcaemia?
they inhibit PGE, OAF (IL-1β), vitamin D, and intestinal calcium absorption.
We should try and reach a diagnosis first, as they can mask lymphoma and provide chemotherapy resistance
what is the most common cause of neoplastic hypoglaemia in the dog?
what are less common causes?
insulinoma
Nonislet cell tumors can also serve as sources of ectopic hormone production with resultant hypoglycemia in dogs and humans. Nonislet cell tumors with PNS hypoglycemia have been most commonly associated with hepatocellular carcinomas; however, lymphoma, hemangiosarcoma, oral melanoma, hepatoma, plasma cell tumor, multiple myeloma, smooth muscle tumors (leio- myoma and leiomyosarcoma), mammary tumors, renal tumors, and salivary gland tumors have also been reported.
what are non pancreatic tumour molecular causes of hypoglycaemia ?
The hypoglyce- mia of extrapancreatic tumors has interestingly been associated with low insulin levels, whereas pancreatic beta-islet cell tumors .
Nonislet cell tumors may induce hypoglycemia by increased tumor utilization of glucose, decreased hepatic glycogenolysis or gluconeo- genesis, or the secretion of insulin or IGF-1 and IGF-2. Additional mechanisms include upregulation of insulin receptors, increased insulin binding by M proteins in myeloma, and increased produc- tion of somatomedins.
what are differentials for hypoglycaemia?
insulinoma, nonislet cell tumor hyperinsulinism, nonislet cell tumor, hypoadrenocorticism, starvation, sepsis, liver dysfunction, toxin, and laboratory error (lack of timely serum separation).
what diagnostic should be performed if hypoglycaemia from neoplasia is syspected ?
Tumors associated with extrapancreatic hypoglycemia are often extremely large, and therefore, radiographs/ultrasound of the abdomen and/or thorax may be helpful.
Provocative testing via glucagon or glucose tolerance testing may be useful in cases when the diagnosis is uncertain.
Ectopic Adrenocorticotropic
Hormone Syndrome secondary to neoplasia is seen in which tumours of dogs ?
reported to occur in primary lung tumors and a single case of an abdominal neuroendocrine tumor.
what are the predominant active molecules in Ectopic Adrenocorticotropic
Hormone Syndrome paraneoplastic syndrome?
why are these important?
CTH, ACTH pre- cursors, endorphins, enkephalins, and melanocyte-stimulating hormone (MSH).
All result in excessive production of steroids from the adrenal glands resulting in clinical signs similar to those seen in hyperadrenocorticism (Cushing’s disease).
How is Ectopic Adrenocorticotropic
Hormone Syndrome diagnosed?
The predominant active molecules in this PNS are ACTH, while Invariably, these tumors are dexamethasone insuppressible.
The diagnosis of this PNS is made by the concomitant presentation of Cushing’s-like signs with an abnormal dexamethasone suppression test and a localizable tumor.
what is the treatment of ectopic adrenocorticotropic hormone?
treatment of choice is removal of the underlying cause by surgical extirpation of the tumor. When necessary, the medical therapy for this PNS centers on inhibiting cortisol production by mitotane or ketoconazole.
what are M-component disorders?
Monoclonal gammopathies - same thing
monocolonal gammopathies can cause hypergammaglobuliniemia. Why and what symptoms do these show?
excessive production of proteins from a monoclonal line of immunoglobulin (Ig)-producing plasma cells or lymphocytes. When production of these Igs, partial Igs, heavy chains, and/or light chains becomes extreme, clinical signs of hyperviscosity (ataxia, depression, demen- tia, cardiac disease and/or failure, seizures, and coma), tissue hypoxia, bleeding (poor platelet aggregation, platelet coating with Igs, and release of platelet factor III), and/or ocular disorders (e.g., papilledema, retinal hemorrhage, detachment) may occur.
how do you diagnose Hypergammaglobulinemia in monoclonal gammopathies?
These proteins may be identified by performing a protein electrophoresis on the serum and/or urine ( light chain production may be detected in the urine as Bence-Jones proteins)
what is the most common cause of Hypergammaglobulinemia?
Plasma cell tumours - e.g. multiple myeloma
what types of cancer can cause Hypergammaglobulinemia
plasma cell tumours (number 1) , lymphomas, lymphocytic leukemias, and primary macroglobulinemia can also cause this PNS.
what are the most common causes of anemia in cance patients?
vast majority are due to either anemia of chronic disease (ACD), immune-mediated hemolytic anemia (IMHA), blood loss anemia, or microangiopathic hemolytic anemia (MAHA).
what are the most common causes for anemia of chronic disease in neoplasia?
This anemia is due to disordered iron storage and metabolism, shortened red blood cell (RBC) lifespan, and occasionally decreased bone marrow response.
what are charachteristics of anemia of chronic disease in paraneoplastic sydnrome?
ACD is normocytic/normochromic, and evaluation of the bone marrow does not suggest significant problems with cellularity.
what are the diagnostics of choice when diagnosing anemia of chronic disease secondary to suspect IMHA in paraneoplastic syndrome?
The diagnosis of PNS IMHA is typically established by a Coombs’ slide agglutination test, and many patients will have con- current spherocytosis and a regenerative anemia.
how do you treat IMHA secondary to paraneoplastic syndrome?
The treatment of choice is removal of the tumor; however, if this is not immediately possible, the use of immunosuppressive dosages of prednisone (1 to 2 mg/kg daily to two times a day by mouth [BID PO]) may be indicated if a diagnosis has been established. Similar to non-PNS IMHA, the use of additional agents such as azathioprine (1 to 2 mg/ kg daily for 4 to 7 days, then 0.5 to 1 mg/kg every 48 hrs PO), cyclosporine, cyclophosphamide, and others may be necessary for complicated IMHA cases
what are charachteristics of RBC in blood loss anemia secondary to parenoplastic cells?
decreased hemoglobin content, the RBCs in blood loss anemia are microcytic/hypochromic. In addition, decreased serum iron, increased total iron-binding capacity, and poikilocytosis may also be noted.
what is the treatment of choice for anemia secondary to blood loss in paraneoplastic sydndromes ?
The treatment of choice is removal of the tumor, although severe anemia may necessitate blood transfusions. The use of oral and/or injectable iron may be a useful adjunct therapy.
what is MAHA ? what is the most common cause ?
Microangiopathic Hemolytic Anemia (MAHA) is a secondary phenomenon to hemolysis and is typically due to fibrin deposition and/or endothelial damage.
The most common causes of MAHA are PNS disseminated intravascular coagulation (DIC) and RBC shearing as the result of hemangiosarcoma
what are common blood film findings in MAHA
Schistocytosis and hemolysis are common indicators of ongoing MAHA.
what is the most common neoplastic cause of DIC and MAHA?
While any tumor can cause DIC and subsequent MAHA, hemangiosarcoma is the most common.
is anemia secondary to chemotherapy common and how severe is it ?
It is common in humans, but not in veterinary medicine. The degree of anemia seen in veterinary cancer patients undergoing chemotherapy is generally mild, with typical packed cell volumes hovering in the 28% to 32% range for dogs and 24% to 28% range for cats.
how common is erythrocytosis as a pareneoplastic syndrome and what are the main causes?
Erythrocytosis (polycythemia) is a relatively uncommon PNS. Tumors that have been associated with PNS erythrocytosis include renal tumors (primary and secondary), lymphoma (including renal origin), lung or liver tumors, cecal leiomyosarcoma, nasal fibrosarcoma, and transmissible venereal tumor (TVT)
M stage is sensitive to what types of chemotherapy ?
Taxanes and Vincas
S stage is sensitive to what types of chemotherapy
Antimetabolites
which stage of the cell cycle is resistant to raditaiton ?
S stage and G0
What chemotherapy agents are effective at all stages through the cell cycle?
platinum analogues, alkalating agents
what is radiosensitatisation via use of chemotherapy ?
use of chemo to increase sensitivity of a cell to radiation
what is consolidation and maintanance chemotherapy?
Consolidation therapy -> re-intensification of therapy after
remission is attained to further reduce the likelihood of relapse
-> Used most commonly with hematopoietic cancers
Maintenance therapy -> also used after remission is attained but involves low-intensity therapy given over a protracted period of time
what is partial remission
decrease in tumour volume >50% or tumour diameter by >30%
what is stable disease?
No change in size - e.g. <30% volume reduction or <20% increase in tumour diameter
what is progressive diasea?
increase in tumour volume >25% or increase in tumour maximum diameter >25%
what is median response duration / median survival time?
the median value for a group of individuals treated with a given therapy in terms of the length of time they achieve a completer or partial remission (MRD) or length of survival after implementation of therapy (MST)
what is progression free interval? and progression free survival?
PFI; the amount of time elapsed without evidence of progressive tumour growth
PFS; survival without progressive growth of the tumour from treatment start
What is disease-free interval / disease free survival?
DFI; the amount of time elapsed without disease recurrence
DFS; the amount of time or survival of the patient after therapy
is tumour growth rate constant ?
no - early on tumours grow exponentially (this is the most effective time to give chemo as they are rapidly dividing)
what is the Gompertzian model of tumor growth
-> Large growth fraction early = more sensitive to chemotherapy
-> Once tumor is detectable = fewer cells dividing
why do large tumours not respond as well to chemotherapy?
Large tumor = high interstitial pressure & less chemotherapy penetration
Goldie-coldman hypothesis?
Tumors are clinically detectable after
30 doublings
-> 1 billion (1 x 10 9) tumor cells
-> 1 gram / 1 cm3
Once the tumor has reached 1 million cells, it is likely that chemotherapy resistant cells have developed due to
mutations
Therefore single agent chemotherapy is
rarely curative
what is MTD?
Maximum Tolerated Dose
Optimized tumor cell kill which requires a break period to allow recovery of normal
cell populations
when should chemotherapy be started?
ASAP - if surgery performed at 10-14 days (suture removal)
if a mass is removed with dirty margins, when can chemo be started and why?
10-14 days. Chemo is often cytotoxic to rapidly dividing cells. If given while the incision is healing this will inadvertently kill the cells trying to close the wound
why are multiple drugs used in chemotherapy regimes?
because there are often mutations confering resistance to one agent.
Drugs with different
mechanisms of action ->
avoids cross resistance
Non-overlapping toxicities
Differing cell cycle specificities
Have to use drugs that would be effective as single agents though
what are cell cycle specific chemotherapies and give examples?
can only act on cells in specific
phase of cell cycle
- Antimetabolites (hydroxyurea)
- Antimicrotubule agents (vinca
alkaloids & taxanes)
what are cell cycle indipendent or non specific chemotherapies and give examples?
active throughout all phases
- Alkylating agents
(cyclophosphamide)
- Antitumor antibiotics
(doxorubicin)
- Platinum agents
(carboplatin)
which chemotherapies target microtubules?
How do these work
Vincristine-> inhibition of microtuble agregation of alpha and beta tubulin -> cell cycle arrest as chromosomes cannot separate
paclitaxel-> inhibition of microtubule disaggregation -> orevent breakdown of tubules post chromosomal division ->cell cycle arrest and apoptosis
which drugs affect mitochondial function and how?
Oxaliplatin, cisplatin, vincristine and paclitaxel -> alter the function of the ETC increasing ROS and resulting in cell death
Oxaciplatin and cisplation; inhibit mDNA replication and transcription
All of these alter mitochondrial function and lead to apoptosis
which chemotherapy targets G1
L-asparaginase
G0 phase is sensitive to what chemotherapies?
it is not, it is resistant
what are the key mechanisms of resistance to chemotherapies?
-Increased drug efflux (increased MDR expression, P-glycoprotein pump)
- Reduced uptake (drugs that require active transport)
- Decreased activation of drug
- Increased drug catabolism
- Increased de-activation (e.g. glutathione binding)
- Increased or decreased target expression
- Increased DNA repair
- Evasion of apoptosis
what mechanism of resistance can inhibit the fucntion of doxorubicin agents?
altered topoisomerase II structure
how is resistance built to methotrexate?
decreased expression of folate transporter prevents drug uptake, or amplified DHFR or TS, or decreased folypolyglutamul synthase
what mutations can confer resistance to most anticancer drugs?
p53 mutations, bcl2 activation or oversupression
what mutation can increase drug efflux conferring resistance? and to what anti-cancer agents?
Increased MDR expression by MDR gene amplification.
Affects doxorubicin, etoposide, vinca alkaloids, pacitaxel, topotecan
what is dose adjustment for renal dysfunction and what drugs does this affect?
decrease dose in proportion to
the reduction in creatinine clearance below 60 mL/min
Affects renally excreted drugs;
- bleomycin,
- carbo and cisplatin
- etoposide
- fludarabine
- hydroxyurea
- methotrexate
- pentostatin
- topotecan
What is dose adjustement for liver dysfunction ?
Drug examples?
Dose reduction of anticancer drugs that require hepatic metabolism cyp450. This is mased on;
1.5-3.0 mg/100 mL -> 50% dose reduction
>3.0 - > 75% dose reduction
- Bunsulfan
- cyclophosphamide
- ifosfamide
- imatinib
- paclitaxel
- thiotepa
- vinca alkaloids
which chemotherapy drugs are secreted in the bile?
doxorubicin
ifinotecan
vinca alkaloids
which chemotherapy drugs are renaly excreted?
- bleomycin,
- carbo and cisplatin
- etoposide
- fludarabine
- hydroxyurea
- methotrexate
- pentostatin
- topotecan
list the chemotherapy agent, the interacting drug and wherther the clearance is clinically significant. In addition state the probable mechanism
what is the toxicity incidence in canine/feline populations?
Overall ~20-30% of canine / feline patients experience some toxicity -> most
are mild, self-limiting, or non-clinical
≤ 5% are severe, often needing hospitalization -> reduce dose,
eliminate drug, stop chemo
≤ 1% are life-threatening
what is drug toxicity dependent on?
Toxicity is patient, drug, and dose dependent
what normal cells are targeted by chemotherapy?
All rapidly dividing cells
- Tumor cells
- Bone marrow stems cells
- GI crypt stem cells
- Growing hair follicle cells
what is BAG of adverse events?
Bone marrow toxicity
Alopetia
Gastrointestinal toxicity
what dogs are mostl likely to affected by alopetia as a side effect?
Breeds with continually growing hair
coats
-> Poodles, Schnauzers, Bichons, Afghans,
Old English Sheepdogs
how does chemo affect the bone marrow?
Chemo affects dividing cells = immature or early precursor cells.
when do you start seeing bone marrow toxic changes in patients on chemo?
Becomes evident in peripheral blood depending on lifespan of cell -> earliest
affected are those being replaced first
WBC t1⁄2 = hours (12-24 hrs)
Platelet t1⁄2 = days (3-4 days)
RBC t1⁄2 = months
Lymphocyte t1⁄2 = years
Some variability in sensitivity to specific drugs
Nadir = low point
Neutrophil nadir = 7-10 days
Platelet = 3-4 weeks
RBC = long survival (mild, low grade)
what is nadir?
and what is it for different cell types?
Nadir = low point
Neutrophil nadir = 7-10 days
Platelet = 3-4 weeks
RBC = long survival (mild, low grade)
GIT toxicity can be acute or delayed. Describe the frequency, drugs that cause each and main treatment;
Acute
- Uncommon
- Direct stimulation of chemoreceptor trigger zone - vomiting
- Ex: cisplatin, streptozotocin, dacarbazine
- Tx = IVFs, prophylactic anti-emetics (i.e. maropitant, ondansetron)
Delayed (2-5 days)
- Common
- Nausea, hypo/anorexia, vomiting, soft stools, diarrhea
- Effect of chemo on GI crypt cells
- Mucositis common in people – basal cells
how does diarrhoea occur secondary to chemo admin?
- Caused by damage to intestinal epithelium
- Small bowel
- Colitis (doxorubicin)
- Manageable with diet alterations, probiotics +/- metronidazole or tylosin
how is vomiting caused by chemo drugs
Direct stimulation of chemoreceptor trigger zone - vomiting
- Ex: cisplatin, streptozotocin, dacarbazine
Or
Local irritation of GI tract days after chemo
Manageable with prophilactic anti-emetics
what is VCOG-CTCAE v2
veterinary cooperative oncology group -common terminology criteria for adverse events
define the VCOG-CTCAE v2 groups;
what does the MDR1 gene encode for, what patients is the mutation found in and what are the at risk drugs for this group ?
Encodes the P-glycoprotein drug transport pump
- Limits drug absorption & distribution, esp. to brain
- Enhances excretion of drugs
MDR1 mutant patients have defective pumps & are more susceptible to side effects
Found in; collies, long haired whippet, australian shepherds (normal and mini)
High risk drugs
- Vinca alkaloids, paclitaxel & doxorubicin -> documented to cause problems
- Etoposide, mitoxantrone -> p-glycoprotein substrates
in humans, unknown in dogs
what NON chemotherapeutic drugs are contraindicated in MDR1 mutation carrying patients
Loperamide (Imodium®), Ivermectin
How can you test for the MDR1 mutation?
MDR1 (ABCB1) allele mutation
test available at washinton state university
if you have a MDR1 mutation, can you give at risk drugs?
homoxygotes yes but dose adjustment is recommended. Unkown the risk for heterozygotes if a full dose is given
what dogs may have adverse reactions to p-glycoportein drugs?
what can you substitute these with
MDR1 mutation carriers
Encodes the P-glycoprotein drug transport pump
- Limits drug absorption & distribution, esp. to brain
- Enhances excretion of drug
Can substitute p-glycoprotein drugs with alkalating agents
what is the neutrophil nadir for vinblastine, vincristine, vinorelibine, doxo, cyclophos, lomustine, carbo?
examples of alkalating agents? and methylating agents?
Nitrogen mustards = mechlorethamine, melphalan,
cyclophosphamide, ifosfamide, chlorambucil
Nitrosureas = lomustine, BCNU, streptozotocin
Non classical alkylating agents (known as methylating agent) = Procarbazine, dacarbazine, temozolomide
what is the mechanism of action of alkylating agents?
Biologic activity results from polyfunctional alkylation of DNA
alkylation of DNA bases through formation of reactive intermediates that attack neutrophilic sites
- Cause inter- and intrastrand cross-links
- Induce apoptosis
where are alkylating agents excreted from?
urine & feces
what is the mechanism of resistance for alkylating agents?
Increased capacity to repair alkylated lesions
- Increased guanine O6-alkyl transferase in nitrosureas & methylating agents
- Increased expression of glutathione-associated enzymes (the glutamyls)
- Increased ALDH = aldehyde dehydrogenase (cyclophosphamide)
- Decreased expression or mutation of p53
- Enhanced DNA damage repair (increased nucleotide excision repair)
- decrease drug uptake (altered leucine pumps)
what are the side effects of cyclophosphamide and ifosfamide agents? how do these occur, how are they treated?
How do you prevent?
How do you diagnose?
what family do these belong to?
They are alkylating agents;
Cyclophosphamide & ifosfamide
- Metabolism = hydrolysis to phosphoramide mustard (active) & acrolein metabolites
- Sterile hemorrhagic cystitis (5%)
- Due to excretion of the metabolite acrolein which directly irritates bladder mucosa
- MESNA (2-MErcaptoethane SulfoNAte) used to prevent SHC – hydrolyzes in urine to yield active parent that conjugates with alkylating species to prevent cystitis
- Prevention: Give Cytoxan in morning, fresh water, prednisone /
furosemide
- Dx & Tx: Culture to rule out UTI, never give drug again!
anti-inflammatories, pain control, anti-spasmodics, time
what are the side effects of lomustine ?
how are they treated?
How do you prevent?
How do you diagnose?
what family do these belong to?
IT is an alkylating agent
Enters cells via passive diffusion
Side effects
- BAG
- Myelosuppression common & often severe - 2/3 dogs develop
-Hepatotoxic
- ≤ 70-80% of dogs develop increases in ALT with repeated doses
- Monitor liver enzymes -> delay/discontinue/dose reduce
what are the side effects of streptozocin?
How do you prevent?
How do you diagnose?
what family do these belong to?
what is it used to treat?
Alkalating agent used to treat pancreatic beta cell tumours
Side effects include pancreatitis and renal toxicity.
Administer IV with diuresis to avoid nephrotoxicity
what are the side effects of chlorambucil agents? how do these occur, how are they treated?
when do side effects occur?
what family do these belong to?
How does it enter the cell?
Brand name?
enters the cell by passive diffusion.
Irreversible thrombocytopenia with chronic tx-> ~40% of dogs on tx > 1 year
Cannot be treated unless a bone marrow transplant is performed.
what is lomustines brand name?
Injectable or ora
CCNU
Oral capsule
what is the most commonly used metronomic chemotherapyh?
cyclophosphamide
How does cyclophosphamide work?
anti-angiogenic cell cycle non specific
Directly binds to blood vessels inhibiting. Suppression of T regulatory
lymphocytes leading to
blood vessel inhibition
what are the 4 alkylators that are pro-drugs that need to be activated
Cyclophosphamide
Ifosfamide
Dacarbazine
Procarbazine
examples of platinum agents?
Cisplatin, carboplatin, oxaliplatin
what is the MOA and MOR of platinum agents?
MOA = Actively transported into and out of the cell. Bind to DNA & form inter- and intra-strand
crosslinks
MORs that result in increased tolerance to DNA
damage:
- Alterations in transmembrane cellular accumulation of drug
- Cytosolic inactivation of drug
- DNA damage repair (increased nucleotide excision repair)
- Resistance to apoptosis
- Cisplatin MOR = defective recognition of DNA adducts (missmatch repair defect)
what are the two configurations of platinum agents what is the difference these provide from a chemotherapy function standpoint?
cis analog = clinically active trans analog = not active
what is the toxicity profile of cisplatin?
How can these be prevented?
BAG
Stimulation of CRTZ -> vomiting, use prophylactic anti-emetics
Nephrotoxicity -> diuresis minimizes the risk
Cisplatin toxicity in cats = Fatal idiosyncratic pulmonary edema
(“cisplatin makes cats go splat”)
what is weird about carboplatins nadir/
unique delayed or double nadir -> 10-14 days, 21 days (up to 28+ days in cats)
which drug has a doubled nadir and what are they?
carboplatin
0-14 days, 21 days (up to 28+ days in cats)
what are antitumour antibiotics and give examples?
Derived from yeast and affect Cell cycle activity in all areas of cell cycle
Doxorubicin, mitoxantrone, epirubicin
what are other names for anthhracyclins?
Antitumor antibiotics / Anthracenediones
brand name for doxo?
adriamycin
what are MOA for anthracyclins?
- Intercalation into DNA
- Inhibition of topoisomerase II & DNA/RNA polymerases
- Alkylation of DNA
- Production of free radicals (except mitoxantrone)
- Cell membrane damage via changes in intercellular calcium homeostasis
what are MOR for anthracyclins?
Glutathione/GSH inactivation, increased drug efflux (increased MDR expression or MDR gene amplification), absent or mutated drug target
what specific toxic side effects fo anthracyclines have?
Cardiotoxicity in dogs (irreversible)
- Typically if cumulative dose >180 mg/m2
(>6 doses)
- Appears clinically similar to CHF & tx is similar
BAG in dog and cat
Nephrotoxicity in cats
Histamine release - anaphylaxis possible (rate of infusion matters)
Severe vesicant if extravasated - COLD COMPRESS
examples of antimetabolites?
5-fluorouracil, cytarabine, gemcitabine, methotrexate, hydroxyurea, Tanovea®
what is the MOA and MOR of antimetabolites?
Toxicities?
Cell cycle phase specific (S phase)
MOA = Nucleotide analogs that resemble DNA
metabolites-> Incorporate into replicating DNA strand to disrupt DNA synthesis
MOR = decreased drug activation, increased
drug target
Toxicities;
- BAG in dogs
- Longer infusion = more myelosuppression
- Do NOT use 5-FU in cats neurotoxicity
What type of chemo is gemcitabine, MOA and MOR
It is an antimetabolite (2,2-difluorodeoxy-cytidine (dFdC) analog)
MOA = incorporation into DNA terminates chain elongation, inhibits ribonucleotide
reductase, depletes physiological deoxynucleotides
MOR = Inhibition of nucleoside transporter systems, deficiency of activating enzyme
(deoxycytidine kinase)
which antimetabolite is a radiosensitizer? and why?
Gemcitabine
most potent before RT, due to ribonucleotide reductase inhibition
what chemotherpy family does cytarabine belong to? what is the other name? MOA and MOR ?
Antimetabolite
Other name; cytosine arabinoside
it is an arabinose nucleoside analogue.
MOA = competitively inhibits DNA polymerase alpha, incorporated into DNA,
terminates DNA chain elongation
MOR = decreased drug activation (decreased deoxycytidine kinase)
What is hydroxyurea and what family does it belong to? MOA and MOR?
Antimetaboline - purine analogue
Enters cells by passive diffusion
- MOA = Inhibits ribonucleotide reductase
- MOR = Increased synthesis of cellular ribonucleotide reductase
What is 5-FU and what family does it belong to? MOA and MOR?
What patients should NOT receive 5-FU
5-Fluorouracil, it is an antimetabolite chemotherapy
Halogenated analog of uracil
MOA = Incorporation of 5-FdUMP into RNA interferes with RNA processing & function;
5-FdUMP inhibits thymidylate synthetase
MOR = Increased drug target (amplified TS)
Do NOT use 5-FU in cats neurotoxicity
what chemo drugs cross the blood brain barrier?
which ones penetrate the CNS?
Lomustine (CCNU)
Cytarabine
Hydroxyurea
Lipophilic & penetrate the CNS -> Procarbazine, temozolomide, dacarbazine
what is methotrexate? what famility does it belong to? MOA and MOR?
antimetabolite Folate analog
- MOA = Inhibits dihydrofolate reductase -> prevents formation of reduced folates
required for DNA synthesis - MOR = Decreased drug uptake (decreased expression of the folate transporter),
decreased drug activation (decreased folylpolyglutamyl synthetase), increased
drug target (amplified DHFR)
what is tanovea ? MOA ? side effects?
rabacfosadine for injection
it is an antimetabolite Double prodrug of the guanine nucleotide analog PMEG which is approved for treatment of canine LSA
MOA= inhibits DNA synthesis by inhibiting DNA polymerases leading to S phase arrest & apoptosis
Toxicity;
- BAG
- ~25% of dogs develop cumulative dermatologic adverse effects
- <5% develop pulmonary fibrosis (not recomended for westies)
in what breed of dog is Tanovea NOT recomended in?
Westies. less than 5% of patients on tanovea will develop pulmonary fibrosis, but it should not be used in an at high risk group
what drugs cause pulmonary fibrosis ?
- Tanovea
- Bleomycin (cumulative)
- CCNU (one cat)
- BCNU
- Hydroxyurea
- Mitomycin C
what are examples of spindle toxins?
Vinca alkaloids-> Vincristine, vinBLASTine, vinorelbine
MOA of Vinca alkaloids?
MOA = Bind to tubulin -> inhibit microtubule assembly -> prevent mitotic spindle formation -> metaphase arrest -> apoptosis
What part of the cell cycle do vinca alakloids target?
M-phase (hence they target spindles)
MOR of vinca alkaloids?
Increased drug efflux (increased MDR expression or MDR gene
amplification), altered drug target (i.e. microtubules)
Toxicity of vinca’s?
- BAG
- Minimally myelosuppressive
- Ileus
- Peripheral neuropathy (rare in pets)
- Tissue irritation if extravasated (vesicant) -> HOT COMPRESS
what are the differences in the treatment of extravasion of doxorubicin and vinca alkaloids?
Doxo -> COLD compress
Vinca -> HOT compress
what are taxanes?
spindle toxins
e.g. Paclitaxel and docetaxel
what are examples of chemo families that are spindle toxins?
examples of each family
Vinca alakaloids ->Vincristine, vinBLASTine, vinorelbine
Taxanes -> Paclitaxel and docetaxel
Examples of taxanes?
Paclitaxel and docetaxel
what is the MOA of taxanes?
Stabilise microtubules->prevent dissassembly of mitotic spindle
what is the MOR of taxanes?
Increased drug efflux (increased MDR expression or MDR gene amplification), altered
drug target (i.e. microtubules)
what are the toxicity profiles of taxane?
- BAG
- Original formulation of paclitaxel causes hypersensitivity due to Cremaphor (whater insolluble adjuvant)
How has paclitaxel been reformulated to prevent hypersensitivity ?
Cremaphor, which was a water insoluble adjuvant which can cause hypersensitivity can be prevented with Paccal Vet-CA1 which is has a water sulluble formulaiton
what is abraxane?
brand name of paclitaxel
give examples of topoisomerase inhibitors?
Camptothecin TOP1 inhibitors
- Topotecan
- Irinotecan
Intercalating and nonintercalating TOP2 inhibitors
- Intercalators = doxorubicin, daunorubicin,
mitoxantrone
- Nonintercalating epipodophyllotoxins =
etoposide, teniposide
what form of topoisomerase 2 inhibitors are there and give examples?
nonintercalating TOP2 inhibitors
- Intercalators = doxorubicin, daunorubicin,
mitoxantrone
- Nonintercalating epipodophyllotoxins =
etoposide, teniposide
what is the MOA and MOR for topoisomerase inhibitors?
MOA= degrade topoisomerase that. TOP1 makes single stranded cuts in DNA, allowing double helix to rotate
TOP2 makes double stranded DNA cuts allowing knots and tangles to be undone.
MOR = Increased drug efflux (increased MDR expression or MDR gene amplification)
what is the toxic profile for topoisomerases?
myelosuppression, GI, elevated liver function tests
what is Elspar?
L-asparaginase
What is L-asparaginases MOA and MOR ?
MOA = depletion of the amino acid asparaginase leads to
inhibition of protein synthesis
MOR (resistance emerges rapidly when used as a single
agent) -> Upregulation of L-asparagine synthetase
- Increased uptake/retention of L-glutamine and L-asparagine by tumor cells
what tumors require L-asparagine?
lymphoma and othe hematopoietic tumours
why is lymphoma sensitive to L-asparaginase?
L-asparagine synthetase is present in normal cells, but not in lymphocytes, hence they are relient on external sources
what chemotherapy is blocked by L-spar?
Methotrexate
what chemotherapy can be given as a rescue agent for methotrexate (MTX) toxicity>
L-asparaginase as this blocks MTX action
what is the toxicity profile of L-apsaraginase (Elspar)?
Minimal toxicity
- hypersenisitivity ->premed with diphenhydramine
- decreased protein synthesis (albumin, insulin, clotting factors, ATIII)
- Pancreatitis
- Nausea, vomiting, fever, chills
how does L-asparaginase work /
L-asparagine cannot enter all the cell. In the blood, L-asparagine is converted into L-aspartic acid by L-asparaginase. L-aspartic acid can then be uptaken by the cell and then bound to L-glutamine, which is converted to L-asparagine + L-glutamine again by L-asparagine synthase
which drugs do you cold compress with extravasation>
Doxo
Dactininomicin
MTX
Danorubicin
Idarubicin
Actinomicin-D
Epirubicin
(all the anthracyclins)
What steps should be taken when there is anthracycline extravasation?
COLD compress for 20min TID for 1-2 days and neutralise with Dexrazoxane
what chemo agents do you HOT compress?
Vincristine, vinblastine, Vinorelebine (all the vins - aka vinca alakaloids) and taxanes
what is the protocol for vinca alkaloid extravasion?
HOT compress area for 20min TID for 1-2 days
what is the protocol for taxane alkaloid extravasion?
HOT compress area for 20min TID for 1-2 days
what are the 3 areas of concern for chemo safety>
1) veterinary staff
2) patient
3) owner
what are the key chemotherapy safety points ;
- all staff needs to be trained
- familiarise yourself with the drugs
- drugs must be stored in a secure place and clearly labeled
- special waste containes
- no drink/food in chemo area
- wash hands before and after
- draw up and under a hood
- use luer lck fittings or ideal PhaSeal or Equashiedl closed systems
- PPE
- Chemo spill kit
Owner safety key points for chemo
- make aware of excretion path
- never crush/cut pulls
- no liquid formulations
- latex gloves to clean urine/faeces/vomit
most drugs pose minimal risk after 72h
what type of chemotherapy is palladia?
it is a tyrosine kinase inhibitor (TKI). KIT is involved in cell grrowth and survival. Also involved in the spread of mast cell tumours .
what is palladias active name?
toceranib phosphate
side effects of palladia?
Diarrhea
Vomiting
Loss of appetite
Weight loss
Skin changes
Bone marrow suppression
what are the indications of palladia?
Palladia is approved for the treatment of grade II or III cutaneous mast cell tumors in dogs, with or without lymph node involvement. It may also be used off-label for other types of cancer in dogs and cats
what is palladia approved for?
approved for the treatment of grade two or three cutaneous mast cell tumors with or without lymph node involvement in dogs
what are palladias MOA?
- Palladia works by inhibiting receptor tyrosine kinases (RTKs), which are proteins that play a role in cell growth and division.
- t also has anti-angiogenic properties, meaning it can help starve tumors by blocking the formation of new blood vessels that supply them with nutrients and oxygen
is palladia a chemotherapeutic
no technically it is an anti-cancer drug as it prevents the formation of new blood vessels which reduces nutrient delivery to the tumour.
oxorubicin (DOX), cis-
platin, carboplatin, and melphalan all are associated with
an increased prevalence of adverse effects in small dogs. Why?
How is this overcome?
Because drugs are calculated on body surface area which is thought to be a better representation of metabolic rate, however, smaller animals have a larger body surface area.
Melphalan overcomes this by being in mg/Kg. The others have a seperate, lower dose per M2 for dugs <10-15kg
what is ABCB1 mutation, what dogs are susceptible and what chemotherapeutics may represent an issue?
which chemo are not impacted?
This is the MDR1 gene mutation, also known as P glycoprotein mutation seen in Collies, australian shephers and long haired whippets.
Vincristine - increase neutrpenia an thrombocytopaenia
DOXO extreme GI tox
Also potentiates Vinblastine, vinorelebine, mitoxantron, dactinomcin, docetaxel, paclitaxel and etoposide
Alkylating agents,
antimetabolites, and platinum chemotherapy drugs are
not impacted by ABCB1.
which chemo drugs are not impacted by the MDR1 mutation ?
Alkylating agents,
antimetabolites, and platinum chemotherapy drugs are
not impacted by ABCB1.
many chemos are myelosupressive. Why do we often seen neutropaenia but rarely see anaemia?
becuase of the half life of cells. RBC half life is a few weeks and thus persist longer in the blood stream compared to neutrophils which have a half life of a few days
what is a recomended test to be performed in cancers which have a high rate of bone marrow infiltration if there are abnormaliteies on CBC?
What considerations need to be made for administering chemo drugs to these patients.
Bone marrow apsirates - especially if cytopaenic.
You may need to administer chemo when they are cytopaenic, but it is ideal to start with less mylotoxic drugs such as L-asparaginase
A CBC should be performed on the day of chemo administration. What should the normal NEU and PLT be?
NEU 500 to 2500/μl and platelet counts should be
50,000 to 100,000/μl or more on the day of treatment.
When should CBC’s be performed for myelosupressive chemo ?
When should it be repeated if there is cytopaenia ?
And when after the admin?
- Day of chemo
- if cytopaenic re-test 3-7 days later
- recheck at nadir for the drug
if you get cytopaenia from a chemotherapeutic (non clinical) what medical intervention needs to be taken
- Antibioitics (high dose NOT reomended) -> amoxyclav/enro/TMS common choises
- Reduce dose of chemo by 10-25% in subsequent treatments (regardless of whether an infection is developed or not)
what is the most common cause of systemic infections with chemo?
Bacterial translocation from gut (sometimes skin) which is usually increased due to damage to the GIT epithelium and coupled with the fact that most chemos are myelosupressive
why are systemically sick patients, post chemo, not always febrile?
becuase the WBC are responsible for fever development and these have been supressed
if a fever and symptoms do not break within 24 of hospitaisation post infection secondary to chemo, what diagnostics should be perfomed?
chest and abdominal imaging to look for a nidus of infection. Blood cultures are not routine
what drugs most commonly cause thrombocytopaenia?
Carboplatin, lomustine, dacarbazine, melphalan, and occasionally DOX
These drugs should
be discontinued in patients with persistent platelet counts below 75,000 to 100,000/μl.
what drugs can cause ACUTE vomiting and how?
These affect the CTZ
Drugs that can cause acute vomiting include
cisplatin, dacarbazine, streptozocin, and occasionally
mustargen and DOX
How does DOX cardiotox manifest as?
Often non clinical and you see systolic duysfunction on echo. Can manifest as arrhtyhmias alone or in combo with signs of DCM
Dox cardiotoxicity, is it dose dependent ?
It is cumulative -> manifests as a decrease in myocardial contractility with
or without secondary arrhythmias
how does DOX’s cumulative cardiotoxicity manifest
primarily by oxidative injury to the sarcoplasmic
reticulum. The heart is particularly susceptible to oxidative injury because cardiac myocytes are rich in ironcontaining proteins (such as myoglobin) that can donate their metal to catalyze strong oxidant formation. Additionally, cardiac tissue has limited ability to scavenge these free radicals: it has very low levels of catalase, and DOX causes a transient drop in the level of glutathione peroxidase.
at what doses do we start seeing DOX cardiomyopathy?
What medication can be administered to potentially reduce cardiotox effect and what is a possible side effect of this ?
cumulative doses above 180 to 240 mg/m2
Dexrazoxane (Zinecard; 10 mg/1 mg of DOX IV) can be administered immediately before DOX to reduce its cardiotoxic effects substantially. In people, there is debate as to whether dexrazoxane can reduce the antitumor efficacy of DOX;
which are the most nephrotoxic drugs and what must be done to minimize side effects of these?
Cisplatin, ifosfamide, and streptozocin all are nephro-
toxic and require intensive saline diuresis during admin-
istration.
Serum creatinine concentration should be measured before each treat-
ment, and these drugs should be discontinued if creatinine concentration becomes elevated.
which drugs should not be administered to patients with renal disease/failiure?
Cisplatin, ifosfamide, and streptozocin all are nephrotoxic
what is a consideration when giving DOX to cats in regards to the drugs toxic profile
In cats specifically, DOX
treatment is associated with cumulative nephrotoxicity.
However, the renal toxicity is neither as consistent nor as rapidly progressive.
It can be used cautiously in cats with underlying renal disease as long as renal parameters are monitored closely
are the platinum agents nephrotoxic?
Cisplatin IS, Carboplatin is NOT
what drugs cause sterile haemorrhagic cystitis and why?
How to prevent this ?
cyclophosphamide or ifosfamide -> Acrolein, an inactive metabolite, can cause direct contact
irritation of the bladder mucoss
K9 receiving standard dose shold be given furosemide (2 mg/kg IV or SC) dilute the acrolein and encourage
urination.
For dogs receiving oral cyclophosphamide at
home, owners should give the medication when they are able to take the dog outside regularly.
Mesna (sodium 2-mercaptoethane sulfonate) binds to acrolein within
the urinary bladder to help prevent irritation
when is 2-mercaptothane sulfonate given to dogs?
This is Mesna. It binds acroelin metabolite from cyclophospamide treatment. Not needed (usually) at normal doses, but maybe used when high doses are given (e.g. high dose pre whole body radiation for lymphoma)
Ifosfamide generates more acroelin than cyclophosphamide so this is more routinely given with this drug
what species is more likely to develope sterile haemorrhagic cystitis ?
lower in cats than in dogs, likely due to differences in their urination behavior
How would you treat the symptoms of sterile haemorrhagic cystitis?
Mesna to bind acroelin
Nonsteroidal antiinflammatory drugs are recommended to reduce
inflammation and pain.
Phenoxybenzamine (dogs:
0.25 mg/kg q8-12h PO) or oxybutynin (dogs: 0.2 to
0.3 mg/kg q8-12h PO) also can help alleviate muscle
spasms.
which drugs are hepatotoxic (frequently used ones). Is this dose dependent?
lomustine - usually cumulative tox, although acute hepatic failiure can occur after one treatment
what blood tests should be performed before each lomustine treatment?
What is the cut off for this marker after which lomustine should be D/C’d
ALT
Can be hepatotoxic.
Not every dog with an elevated ALT concentration develops clinical hepatic failure. However, if ALT level is four or more times the upper limit of the normal reference range, further treatment with lomustine should be discontinued
what medications can be given with lomustine to minimise the risk of toxicity?
Lomustine is hepatotoxic.
Denamarin, a nutraceutical
containing S-adenosylmethionine and silybin, decreases the risk that ALT will become elevated and reduces the magnitude of any elevations in ALT, AMT, BIL, ALP
List the 4 types of hypersensitivities, what immune complex causes them and examples of clinical signs?
Type I) Immediate hypersensitivity -> IgE. hay fever, anaphylaxis, hives
Type II) Cytotoxic hypersensitivity -> IgG or IgM; blood transfusion reaction, autoimmune disease (myasthenia), chemo
Type III) Immune complex hypersensitivity -> mediated by immun complexes (antibody-antigen complex)
Type IV) Delayed T-type hypersensitivity -> T-cells; contact dermatitis, tuberculosis
which chemo are most likley to cause anaphylaxis and what type hypersensitivity and imune complex cause these?
How can you reduce the risk of this occuring?
- L-asparafinase is the main
- Type I hypersensitivity caused by IgE
- Give diphenhydramine as a pre-treatment (15-30min pre)
Dox,Docetaxel, paclitaxel, and etoposide can cause anaphilactoid hypersensitivitiues manifested by head shaking,
flushing, pruritus, or urticaria
what is the cause of the hypersensitivity reaction behind docetaxel, etopiside and paclitaxel ?
Reactions against polysorbate 80 (carrier molecule) for docetaxel and etopiside .
Chemophor EL carrier is behind paclitaxel
why may doxo cause anaphylaxis? when should you premedicate with diphenhydramine?
Rapid administration can cause non–immunoglobulin
E–mediated mast cell degranulation. Pretreatment with
diphenhydramine typically is not needed as long as the
drug is administered over at least 20 to 30 minutes,
what drug can be given in combination with Docetaxel to reduce the risk of anaphylaxis and improve oral bioavailability ?
What is a possible side effect of this
cyclosporine
Increases incidence of GIT side effects
which are the most common vescicants used?
Vincristine, vinblastine, vinorelbine, DOX, epirubicin,
dactinomycin, and mustargen are vesicants.
Think alkylating agents and vincas
which commonly used chemotherapeutics are tissue irritants when given IV
Mitoxantrone, cisplatin, dacarbazine, docetaxel, paclitaxel, and
streptozocin
how to minimise extravasion ?
what should be done if extravasation is confirmed?
what should not be done if extravasation is suspected?
- clean stick
- vein must not have been used in previous 24h
- patentcy assessed by drawing back never flushing
If extravasion occurs
- draw back as much chemo as possible
- aspirate while catheter is slowly removed
- f a subcutaneous blister persists, additional aspirations can be performed using a new needle and syringe each time.
What should not be done
- flush forwards to confirm patency
- Moist compresses and occlusive ban-
dages should not be used because they can further spread
the extravasated drug and worsen tissue damage.
How long can it take for extravasion to become fully evident?
How should the wound be treated?
1-2 weeks
A tissue slough should be treated like any other open wound with débriding as needed, pain medications, and
antibiotic therapy. In severe cases, amputation might be
required.
what special actions should be taken if you have extravasion of vincristine, vinblastine and vinorelebine
-Aspirate as much chemo through catherer as possible
- chemo maybe aspirated by seperate needle aspiration if a bleb is present
- Immediately after extravasation 6 ml of saline can be infused around the affected area, divided into four to six small injections and using a new needle for each one
- sodium hyaluronidase (150 U/1 ml of extravasated drug)
to the saline has been reported, but it is not widely available.
- Warm compresses should be applied to the affected site four times a day, 1 hour initially and then 20 minutes all subsequent times, for 3 to 5 days.
- Dimethyl sulfoxide (DMSO) and fluocinolone ace-
tonide (Synotic) mixed with 10 mg flunixin meglumine (Banamine) should be applied topically after each heat application
what should be done for extravasion of Doxo, Epirubicin and Dactinomycin?
-Aspirate as much chemo through catherer as possible
- COLD compress for 1h intially, then 20min 4x per day for 3-5 days
- DMSO of questionable benefit
- Dexrazoxane 10mg/1mg DOX, should be given at time of extravasion IV, and then repeated at 24h and 48h
what should be done when there is extravasion of Mustargen
sodium thiosulfate
(0.17 mol/l, or 2.5%) should be administered through the catheter before it is removed, or it can be injected directly
into the affected site after the catheter is removed
what are cat specific chemo toxicities ?
Cisplatin should not be given intravenously to cats because of the potential for fatal pulmonary edema
Cysplatin makes Cats go splat
5-fluorouracil is contra-
indicated because of the high incidence of fatal neurotox-
icity with systemic or topical use
what is the Oncept vaccine?
first canine anti cancer vaccine which targets MELANOMA antigen (tyrosinase) for immune recognition by T-cells. Form of immunotherapy
What cell populations does immunotherapy “target”?
What is the purpose of targeting these cells
Natural killer cells, macrophages, and dendritic cells are the primary effector cells responsible for generating antitumor activity following the administration of nonspecific immune activators.
Release of innate immune cytokines, especially
interferon-α (IFN-α) and IFN-γ, also contributes significantly to antitumor activity by suppressing tumor cell growth and by inhibiting tumor angiogenesis.
what are key targets for NON specific immunotherapy drugs?
Toll like receptors (TLR) and Nucleotide-binding oligomerazation domain-like receptors (NLRs)
- TLR 3; activated by double-stranded RNA from viruses
- TLR4; activated by lipopolysaccharide
- TLR 7 and 8; activated by viral nucleic acids and
synthetic molecules such as imiquimod - TLR 9; activated by bacterial DNA
while NLRs
- expressed in the cytoplasm of immune and non immune cells recognize bacterial wall peptides Nod1 and Nod2, as well as viral nucleic acids (retinoic acid- inducible gene RIG1)
what is a key cytological charachteristic of malignant effusions?
How do these effect prognosis?
they are protein rich exudates
they are a negative prognostic indicator
what neoplasias commonly cause effusions in dogs anf cats?
similar for both
- lymphoma most common
- Carcinoma associated (carcinomatosis) second, mostly from metastasis of mammary, ovarian, pulmonary, urothelial, hepatic, or gastrointestinal carcinomas
- Sarcoma associated are rare but maybe seen with metastatic lesions
what is a carcinoma, sarcoma, and adenoma ?
Carcinoma is cancer that starts in the epithelial cells (lining of organs and skin), sarcoma is cancer that starts in connective tissues (bone, muscle, fat), and an adenoma is a benign (non-cancerous) tumor that develops from glandular tissue
what is the average survival of humans with malignant effusions?
5 months
Most common reasons cancer causes effusions?
Most common cause
- Lymphatic infiltration and obstruction in addition to increases lymphatic and vascular permeability
- metastasis to lymph nodes causing obstruciton
- in addition to decreased lymphatic drainage increased angiogenesis results in more fluid production
Other less common
- implantation of tumour cells onto surfaces causing inflammation ( e.g. mesothelioma)
- obstruction of venous drainage -> oedema
why does vascular permeability increase with cancer?
vascular endothelial growth factor [VEGF]) is produced by tumor cells, mesothelial cells, macrophages, monocytes, and tumor-infiltrating T lymphocytes. VEGF induce
the proliferation of new vasculature, which is more
permeable than normal vessels and it also increases the permeability of existing vasculature.
what is VEGF?
Vascular endothelial growth factor -> commonly secreted by tumours to promote angiogenesis. Additionally, the new angiogenic vessels are leaky, and VEGF increases leakiness of pre-existing vessels which leads to malignant effusions .
when is a malignant effusion most likely to contain neoplastic cells?
If there is diffuse
involvement with implanted cancer cells on the parietal
and visceral surfaces. Therefore cancer cells are
more likely to be found in ascitic or pleural fluid of
patients with carcinomatosis (97%) than in the fluid of
patients with lymphoma and those with deep visceral
(e.g., pulmonary or liver) metastases.
if you have a chylous effusion and you suspect neopleasia but is not positive for neoplastic cells, what tests can you perform to identify the most likely cause of this? what is the most likely neoplasm to cause chylous effusion ?
Lymphoma.
If no cells seen on cyto; immunohisto can be performed using CD3 and CD79a (or other Blymphocyte markers) as well as stains for intermediate filaments (e.g., cytokeratins,
which are markers for epithelium-derived cells).
May help differentiate between carcinoma and lymphoma.
Other tests include PCR (testing for antigen receptor
rearrangements ) and flow cytometry
why is it difficult to diagnose mesothelioma in an effusion ?
Both thoracic and abdo surfaces have mesothelial cells. These become reactive in effusions and are hard to differentiate betwen just being reactive and neoplastic
what is pleurodesis ?
treatment for re-occuring thoracic effusions.
introduction of sclerosing
agents may create attachment of the visceral and parietal pleural surfaces, which prevents fluid accumulation
Bleomycin and tetracycines have been used (70% success). Humans use absbestos-free sterilized Talc which has an 80-100% success rate. Not thought to be as successfull on dogs (used to treat chylous effusuon though)
are pleuroperitoneal shunts commonly used to treat pleural effusion?
No, they have a 23% risk of major comlications. Some studies show complications as high as 73%
If you have confirmed neolastic cells on an effusion, what localised treatment options can be performed to reduce the effusuion?
- pleurodesis
- intra cavitary chemotherapy (Cisplatin [not in cats], bleomycin, 5-fluorouracil, thiotepa, and doxorubicin
what drugs can be given in dogs and cats intracavitary for the treatment of effusions?
Dog; Cisplatin, bleomycin, 5-fluorouracil, thiotepa, and doxorubicin
Cat; same, but you cannot give cisplatin (fatal pulmonary oedema develops).
Doxo can be used, but in general it is not recomended due to the risk of tissue necrosis
why is it possibly beneficial to give an intracavitary chemo agent?
The superficial cells causing effusions are likely less perfused and giving intracavitary drugs will expose them to a significantly higher concentration of drug which is not going systemically
why should intracavitary chemo drugs be suspended in 0.9% saline and the line primed with saline prior to infusion being started? what volume of saline should be used ?
Priming the line with saline reduces the risk of chemo exposure when it is placed in the patient and we are checking that there is approrpriate fluid flow.
250ml/2 for thorax, 1000ml/2 for abdomen - these volumes allow distribution of the drug without clinical signs of effusions to develope
why are hepatic neoplasias particularly good candidates for interverntional radiology TACE, TAE etc ?
75-85% of the liver blood supply comes from the portal system, while 85-100% of the neoplasms comes from the hepatic artery. This allows the blood supply
to a hepatic tumor can be interrupted and the normal
liver can remain virtually unaffected
how can interventional techniques help improve the efficiency of radiation therapy in chemo resistant drugs?
Intraarterial delivery of a radiosensitizing chemo-
therapeutic agent such as cisplatin directly to a tumor
that is being irradiated may improve the efficacy of RT. A
combination of intraarterial chemotherapy and RT has
been described in several clinical reports
How do drugs like cisplatin increase radiosensitivity of a tumour?
Cisplatin can induce cell cycle arrest, specifically at the G1-S phase, a time when cells are more sensitive to radiation
Hypoxia: Cisplatin can increase the sensitivity of hypoxic tissues to radiation by generating reactive oxygen species (ROS) (radiation generally does not work as well in tissues that are O2 poor)
Cisplatin lesions can inhibit the DNA-PKcs kinase, a key enzyme involved in NHEJ, a major DNA repair pathway
what is toceranib?
Palladia; rally bioavailable small-molecule inhibitor that blocks a variety of receptor tyrosine kinases (RTKs) expressed on the
cell surface by acting as a reversible competitive inhibitor of ATP, thus preventing downstream signaling.
Toceranib mainly inhibits;
- RTKs
-VEGF-R2
- PDGFRβ (platelet derived growth factor receptor ß)
- KIT
- JAK
what is unusual about Toceranib dosing?
start at 3.5mk/kg q48 and then reduce based on clinical adverse effects (most drugs you start low, work up).
what are adverse effects of toceranib?
D+, anorexia, lameness, weight loss, and hematochezia
What are the excretion times for Carbo, Cycloph, Doxo, Vinblastine, Vincristine (in days post admin and through what secretion)
Carb -> urine, faeces, sebum, cerumen -> 21 days
Cyclo -> urne ->1-4days
Doxo-> urine -> 21
Vinbl-> urine -> 7
Vinc -> urine -> 3
What are the benefits of targeted therapy ?
What are examples of targeted therapy?
Monoclonal antibodies -> eg RituxiMAB
Small molecular inhibitors -> eg ToceraNIB
These are drugs that target cancer-specific proteins, cancer-upregulated pathways, or cancer-signaling pathways, so the drugs are very specific and should target just neoplastic cells. This should reduce side effects (some of these pathways are found in normal cells though).
What is the role of tyrosine protein kinases?
They phosphorylate tyrosine molecules and are expressed on the cell surface, cytoplasm or nucleus. Those on the surface are receptor tyrosine kinases (RTK) and bind growth hormones. These are very important receptors for cancer growth/upregulation and angiogenesis
what are key receptory tyrosine kinases in tumour growth ?
c-kit -> gastrointestinal stromal tumour, mast cell neoplasia
BCR-ABL -> chronic myeloid leukemia (dogs)
EGFR (epidermal growth factor) -> carcinomas like breast cancer, lung cancer, head and neck but also some sarcomas like haemangio
B-raf -> melanoma (humans
Met -> osteosarcoma (dog)
What drug targets BCR-ABK?
Glivac (imatinib) - targeted ATP pocket of ABL, preventing phosphorylation of the signal.
This can also target ckit
What chromosomal mutation has been associated with canine chronic myeloid leukemia ?
Translocation of BCR-ABL between chromosome 9 and 26
what does toceranib target in dogs mutation and cancer type wise?
Targets c-Kit ( on target ) RTK which is essential for mast cell tumour survival. 30% of dogs will have mutations of c-kit which makes the tumours more aggressive but also good targets for small molecular inhibitors.
Off target effects include PDGFR, FLK-1 and VEGFR2 (last is antiangiogenic)
Tocernamid was developed to target mast cell. However, on the dose finding studies, other neoplasias were also targeted. Which ones?
AGASACA, Thyroid Carcinoma, head/neck carcinoma, nasal carcinoma
what is the toxic profile of palladia??
50% D+
40% anorexia
5-30% vomiting
46% neutropenia at maximum tolerated but we use lower ->still monitor CBC
15% hindlimb weakness, pain and tremors
Proteinuria, pancreatitis, GI perf also reported (biochem done to monitor and some will give famotadine or omeprazole off the bat)
when do recheck on patients which are been given palladia?
Why check so often if these drugs are meant to have low toxic profiles
CBC , body weight @ 2 weeks then every 4 weeks for 3 months, then 8-12 weeks (PE, CBC/chem+UA)
D+ can still happen in ~50% of cases, while anorexia 40% and vomiting 5-30%. Neutropenia at high doses is also seen in 46% of cases.
50% will need a dose reduction or a drug holiday during treatment
How often do you re-stage?
depends on tumour type and condition of the dog/cat. Avg is every 3 months at UMN
what is verdinexor?
Laverdia - it is small molecular inhibitor of the nuclear export protein XPO-1. This XPO-1 is responsible for transporting tumour suppressor proteins out of the nucleus (p53, p21, RB, FOXO). By inhibiting XPO-1 we are trying to keep these proteins inside the nucleus.
what is the main side effect of laverdia ?
OTher name for laverdia?
Verdinexor can cause hyporexia at high doses
what is verdinexor used for?
treatment of lymphoma in addition to multimodal chemo or if they did not want to do chemo
what are the 3 main immunotherapy treatment approaches;
1) non specific; increased immune system activation -> increases risk for autoimmunity. Not target enough for onco therapy
2) monoclonal antibodies
3) active immunotherapy; using cancer vaccines (using whole tumour cells or tumour cell lysates to make an autologous vaccine / allogenic [different patients tumour] vaccine) -> Onsept is one of these
what are two types of monoclonal antibodies seen in vet med, what are they used for and what is the efficacy?
Blontress (Aratana) -> chimeric AB against CD20 for canine B cell lymphoma. Does not have reproducible efficacy over 7 IV injections. it is safe
Tactress-> chimeric AB against CD52 for canine T cell lymphoma. Efficacy also not reproducible
what are immune checkpoint molecules that downregulate the immune system?
Why are these important in oncology?
These are the immunological breaks that downregulate the immune system. Tumour cells often upregulate these and therefore the remove the breaks, or in some cases upregulate them so that things like lymphocytes struggle to get activated
- CTLA-4 (cytotoxic T-lymphocyte associated protein 4
- PD1 (programmed cell death)
- PD-L1 (ligang for PD1, found in canine melanoma, MCT and renal carcinoma)
How do you normally determine response to treatment and why may this technique be an issue if immunotherapy becomes common?
MEasuring the mass size and seeing for shrinkage.
This is a problem for monoclonal antibodies as these can recruit immune cells to the tumour causing it to grow. There are no current guidelines for immunotherapy
what are sources of tumour antigens for neoplasia vaccines?
- whole cell ro tumour lysate
- peptide antiges
- plasmid DNA
- Immune cells activated against a turmour
what does the oncept vaccine target ?
when do we give it
Tyrosinase is involved in the production of melanin and is therefore specifically expressed on melanocytes (normal and cancerous) -> melanoma, especially pigments, have overactivation of this. However, it contains human tyrosinase which cross reacts so the dog should build an immune reaction against it. Used in stage II or III melanoma in conjunction with local control
what is the Oncept vaccine efficacy?
Controversial, some studies find benefit, others not. MST 475 days
what is the log kill hypothesis?
establishes that chemo kills a constant fraction of the tumour cells, rather than a constant total number of tumour cells. Thus the kill number is proportional to the number of cells present and changes in proportion to tumour growth.
In the case of leukemias, where the cell growth is exponential, the kill number for a given dose of chemo is logarhythmic. This is not the same for all solid tumours
Examples of alkylating agents?
Cisplatin, oxaliplatin, carboplatin, chlorambucil, cyclophosphamide, mechlorethamine, and melphalan
Examples of anthracyclines
doxorubicin, epirubicin and idarubicin
What do
Alkylating agents do?
Examples?
inhibit DNA transcription into RNA, preventing protein synthesis and the production of new cells
Cyclophosphamide
Ifosfamide
Mechlorethamine
Chlorambucil
Melphalan
What do anthraciclines do?
disrupt cancer cell DNA by poisoning topoisomerase, an enzyme that unwinds DNA for replication.
What are mutations that have been associated with the development of haemangiosarcoma?
Inactivation of p53 and PTEN inactivation are associated with malignant transformation in vascular endothelial cells
Over expression of VEGF (vascular endothelial growth factor) and VEGF1R (vegf receptor 1) which increases vascular proliferation
Basic fibroelastic growth factor which also has angiogenic properties
Matrix metalloproteinases have been shown to increase and have a role extracellular matrix protein breakdown
