Cancer Chemo Principles Flashcards
Cancer chemotherapeutic agents kill by what order kinetics? Describe what this is
Kills by First Order Kinetics
- a given dose kills a constant percentage of cells, NOT a constant number
- if an agent kills 99.9% of tumor volume
- 106 –> 10 <span>3</span>
- 103–> 100
- this means that the same dose which decreases the tumor burden from ^6 to ^3 will be needed to decrease the burden from ^3 to ^0
Definition of growth fraction. What are the implications of it?
Growth fraction:
- proportion of cancer cells that are actively proliferating/dividing at a given point of time
- represents dividing cells sensitive to chemotherapy
- a higher growth fraction causes more cancer cells to be killed when they are exposed to specific drug
Definition of mass doubling time
Mass doubling time:
- time required for a mass to double its volume
- 1/growth fraction
- dependent on the number of dividing cells
- inversely proportional to growth fraction, so tumors with shorter mass doubling times = more amendable to chemo
Gompertzian Growth Curve
Over time, the growth fraction of the tumors **decreases **such that the peak growth rate occurs before the tumor is detectable
growth fraction is only about 1-4% when tumor is detectable
What is the rationale for debulking and adjunct chemotherapy?
debulking= surgical removal of part of malignant tumor which cannot be completely excised, to help enhance effectiveness of chemo
This is done due to concept of Gompertzien growth curve: over time, growth fraction of the tumors decreases. That way, in doing surgery first, there are smaller cells left that are more likely to be proliferating and growing more, thus more responsive to chemo
Mechanism of action of methotrexate
Methotrexate is an antimetabolite:
Folic acid analog: inhibits dihydrofolate reductase –> decreases dTMP –> decreases DNA and protein synthesis
recall DHF reductase converts dihydrofolate to tetrahydrofolate
Major side effect of methotrexate
- myelosuppression, which is reversible with leuocovorin (folonic aid)
- bone marrow
- hepatic
- nephrotoxicity
- **stomatitis **(inflammation of mouth and lips)
- gastrointestinal
- macrovesicular fatty change in liver
- mucositis
- teratogenic
Major side effects of Cisplatin/Carboplatin (alkylating agent)
- nephrotoxicity
- hypomagnesemia (goes together with hypocalcemia and hypokalemia, get decrease in PTH release)
- ototoxicity
- neurotoxicity (stocking and glove sensorimotor neuropathy)
- intensely emetogenic (vomiting inducing)
Major side effects of Vincristine/Vinblastine (antimitotic agents)
- peripheral and autonomic neuropathy
- vinblastine myelosuppression
Major side effects of Daunorubicin/Doxorubicin (antitumor antibiotics, anthracyclines)
- myelosuppression
- cardiomyopathy
Major side effects of Bleomycin (antitumor antibiotic)
- pulmonary toxicity, may progress to pulmonary fibrosis
- little myelosuppression
What type of malignancies are hormonal therapies used for?
Hormonally regulated organs. Used in breast, prostate, ovarian, and uterine malignancies
In breast cancer, list the main drug that is a selective estrogen receptor modulator
Tamoxifen
In breast cancer, list the 2 main aromatase inhibitors. What step is this and where does it occur?
- Exemestane, Anastrazole
- occur outside the nucleus: aromatase convert androstenedione and testosterone into oestrone and cestradiol before entering the nucleus and binding to estrogen receptors.
List the 3 main types of targeted therapies for prostate cancer
- LHRH analog (leuprolide)
- Androgen receptor inhibitors (bicalutamide, enzalutamide)
- 17-a hydroxylase/C17,20 lyase inhibitor (abiraterone)
Hormone therapy toxicities:
Tamoxifen (breast) (7)
blood clots, stroke, uterine cancer, cataracts, hot flashes, joint pain, leg cramps
Hormone therapy toxicities:
Exemestane (breast) (3)
Anastrazole (4)
Exemestane: hot flashes, arthralgies, osteoporosis
Anastrazole: hot flashes, arthralgies, fractures, cataracts
Hormone therapy toxicities:
Leuprolide (prostate) (5)
-hot flashes, impotence, weakness, cardiovascular disease, osteoporosis (LHRH analog, lowering their testoering levels so low)
Hormone therapy toxicities:
Bicalutamide (prostate) (5)
-hot flashes, weakness, liver failure, arthralgias, edema
Hormone therapy toxicities:
Abiraterone (prostate) (4)
-arthralgies, edema, diarrhea, hypokalemia
4 main types of immunotherapy
- monoclonal antibodies
- vaccines
- immunomodulatory drugs
- checkpoint blockade
two main types of immunomodulatory drugs
- IL-2/interferon
- thalidomide and derivatives
suffixes for the following:
- human
- murine
- chimeric
- humanized
- human: umab
- murine: momab
- chimeric: ximab
- humanized: zumab
the more humanized, the less likely you’re going to see a big reaction when we infuse them
mechanism of action of monoclonal antibodies
- prevent cell proliferation
- antibody-dependent cell mediated cytotoxicity (ADCC)
- complement-dependent cytotoxicity (CDC)
Rituximab:
- target
- disease
- side effects
- target: CD-20 (B-cells)
- disease: CD-20+ lymphoma
- side effects: infusion reactions, B-cell depletion
(premedicate with steroids, benedryl, H2 blockers)
Bevacizumab
- target
- disease
- side effects
- target: VEGF (Vascular endothelial growth factor)
- disease: colorectal, non-small cell lung, renal
- side effects: impaired wound healing, thrombosis, HTN, proteinuria
Trastuzumab
- target
- disease
- side effects
- target: HER-2/neu (human epidural growth factor) receptor
- disease: breast, gastric
- side effects: infusion reactions, cardiac (significant cardiomyopathy, HER-2 is normally express in cardiac tissue)
Cetuximab:
- target
- disease
- side effects
- target: EGF receptor
- disease: colorectal, head and neck, pancreas, non-small cell lung
- side effects: rash, fatigue
Reason for cetuximab rash
epidermal growth factor, targeting the skin.
Rashes have the highest response rates, so rash is a good sign
Ipilimumab
- target
- disease
- side effects
- target: CTLA-4 (cytotoxic T-lymphocyte antigen-4)
- disease: metastatic melanoma
- side effects: colitis, dermatitis, hepatitis, neuropathy
CTLA4 are “brakes” on the immune system. The body has to appropriately shut itself off. Antibody blocks this so it cant shut itself off.
Pembrolizumab
- target
- disease
- side effects
- target: PD-1 (programmed death receptor-1)
- disease: metastatic melanoma
- side effects: pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyper or hypothyroidism
PD-1 acts as an invisibility cloak to the cancer cells. Cancer cells express these receptors, and they blanket the cancer so the immune system no longer see it. Antibodies target these receptors to this cloak
Prostate Cancer Vaccine
- name
- how it works/ what it targets
- side effects
Sipuleucel-T
- WBCs are drawn from pt, locate certain immune system cells
- cells are exposed to protein found in prostate cancer cells: prostatic acid phosphatase (PAP)
- alert the immune system, cells put back in patient, stimulate T cells to recognize any cells expressing PAP, attacking cancer cells
- Fever, chills, headache, flu-like illness, myalgies, HTN, hyperhidrosis, groin pain
IL-2:
- disease
- toxicity
- renal, melanoma
- severe capillary leak syndrome (when you give IL-2, youre basically causing sepsis. pressors on protocol, can’t give to everybody)
Interferon
- disease
- toxicity
- renal, melanoma, CML, hairy cell leukemia
- flu-like symptoms, fatigue
Thalidomide and lenalidomide
- disease
- toxicity
- MDS, multiple myeloma
- teratogenesis, peripheral neuropathy, sedation, constipation, venous thromboembolism
Molecularly targeted agents (7)
- targeted toxins
- differentiation agents
- proteosome inhibitors
- Histone deacetylase (HDAC) inhibitors
- Tyrosine Kinase inhibitors (TKIs)
- mTOR inhibitors
- DNA methyltransferase inhibitors
Retinoids: all trans-retinoic acid (ATRA) aka Tretinoin
- Mech of action
- uses
- side effects
- targets PML-retinoic acid receptor (RAR-a) fusion protein (15;17) allowing DNA transcription, inducing differentiation of promyelocytes
- acute promyelocytic leukemia (APL), aka AML-M3
- differentiation syndrome, teratogenic
in Acute promyelocytic leukemia, where does the cell get “stuck” in differentiation?
gets stuck at “neutrophil promeyelocyte” stage: in between myeloblast and N. myelocyte
Differentiation Syndrome: describe the scenario and common mistake for treatment
after getting treated with ATRA/tretinoin for APL:
on day 4, higher white count, now the differentiatl has changed such that you have 90% normal cells, indicating that you’ve had differentiation. But x-ray shows bif fluffy infiltrate on xray, short of breath, hypoxic
Common mistake is to think the patient has fluid overload, and to give lasix/diuertic. This is WRONG. The patient has differentiation syndrome: more mature cells, they’re having problems, so you need to give high dose steroids
Arsenic trioxide
- mech of action
- disease
- side effects
- induced degradation of PML-RARa fusion protein
- apoptosis via mitochondrial-dependent pathway
- disease: APL aka AML-M3
- side effects: differentiation syndrome, prolonged QTc, neuropathy, hyperglycemia, musculoskeletal pain
List the 4 important tyrosine kinase inhibitors
- imatinib
- erlotinib
- crizotinib
- sunitinib
Imatinib mechanism of action
inhibits constitutively active bcr/abl (9,22/philadelphia chromosome) tyrosine kinase, which inhibits proliferation and causes apoptosis
diseases treated with Imatinib
CML (brc-abl)
Ph+ Acute lymphocytic leukemia (ALL)
GIST (c-kit) = gastrointestinal stromal tumor)
dermatofibrome protuberans (PDGFR)
Side effects of Imatinib
edema, nausea/vomiting, muscle cramps, diarrhea, rash
Similar agents to Imatinib
Nilotinib
bcr-abl, c-kit, PDGFR-B - CML
prolongs QTc
_Dasatinib _
bcr-abl, c-kid, PDGFR-B, src -CML, Ph+ ALL
pleural effusions
Erlotinib
mechanism of action
inhibits intracellular phosphorylation of tyrosine kinase associated with EGFR
Erlotinib:
Diseases
Non-small cell lung cancer (NSCLC), pancreatic cancer
Side effects of erlotinib
rash, diarrhea, anorexia, dyspnea, cough, nausea/vomiting
Similar agents to Erlotinib
Lapatinib (also targets erbB2)- Her2+ breast cancer
hand-foot syndrome
Crizotinib
Mechanism of action
Targets ATP-binding pocket of constitutively active TK of fusion gene between EML4 and ALK (anaplastic lymphoma kinase)
Crizotinib:
Disease
Metastatic NSCLC (EMLL4-ALK gene+)
clinical trials in anaplastic large cell lyphoma and neuroblastoma
Side effects of crizotinib
edema, fatigue, increased liver enzymes, anorexia
Sunitinib
mechanism of action
inhibits TKs implicated in metastasis, cell growth and angiogenesis, inhibits phosphorylation (PDGFRa, PDGFRB, VEGFR1, 2, and 3, KIT, FLT3, RET)
Sunitinib:
Diseases
Renal cell carcinoma, gastrointestinal stromal tumor (GIST), pancreatic neuroendocrine tumor (PNET)
Sunitinib side effects
fatigue, diarrhea, neutropenia, stomatitis, hand-foot syndrome, thyroid dysfunction
