6,7 - Introduction to Anemias, hemolytic anemias, other anemias, Chemotherapies Flashcards
Anemia
- Definition – decrease in circulating erythrocyte mass
- Indicated by a decreased RBC, HGB, and/or HCT
- Functionally, decreased oxygen-carrying capacity
leading to tissue hypoxia
Anemia – Compensatory Mechanisms
- Shift to right in oxygen dissociation curve
- Decreased pH
- Increased 2,3-BPG concentration
- Increased cardiac output/heart rate
- Increased respiratory rate
- Shunting of blood to vital organs
- Increased erythropoietin synthesis (kidneys)
Hypoxia-Inducible Factor 1
- Upregulated by hypoxia
- Transcription factor:
- Erythropoietin (increased erythropoiesis)
- VEGF (increased angiogenesis)
- Vasoconstriction of cutaneous and splanchnic
vessels (pallor and decreased renal perfusion)
Anemia – Clinical Manifestations
- Severity of anemia
- Hgb > 10 g/dl – minimal symptoms
- Hgb 7-10 g/dl – tachycardia, shortness of breath
- Hgb < 7g/dl – symptoms related to hypoxia
(weakness, angina, dizziness, fainting) - Rate of onset of anemia (acute vs chronic)
- “It’s not how low you go, it’s how fast you get
there”
Anemia - Classification, Pathophysiologic
- Pathophysiologic
- Decreased production
- Ineffective production
- Increased destruction
- Acute blood loss
Anemia - Classification
* Morphologic
- Morphologic
- Size (microcytic, normocytic, macrocytic)
- Hemoglobin content (hypochromic, normochromic,
hyperchromic) - Shape (poikilocytosis)
Anemia - Reticulocytes
- Helpful in classifying anemias
- Decreased (decreased/ineffective production)
- Increased (increased destruction, acute blood loss)
Anemia – Laboratory Evaluation
- CBC
- Blood smear review
- Iron studies
- Serum vitamin B12/folate levels
- Hemoglobin analysis
- Direct antiglobulin test (Coombs)
- Serum haptoglobin
- Serum bilirubin
- Serum lactate dehydrogenase
- Bone marrow examination
Anemia - Classification
* Morphologic
* Size (microcytic, normocytic, macrocytic)
- Size (microcytic, normocytic, macrocytic)
Anemia - Classification
* Morphologic
* Hemoglobin content (hypochromic, normochromic,
hyperchromic)
Hemoglobin content (hypochromic, normochromic,
hyperchromic)
Anemia - Classification
* Morphologic
* Shape (poikilocytosis)
Red blood cell inclusions
Howell-Jolly bodies (nuclear remnants seen with hyposplenism) depicted below (left) and basophilic stipppling (aggregates of ribosomes/ribosomal RNA seen with thalassemias and lead
poisoning) on right
Hemolytic Anemia (Hemolysis)
- Definition – anemia resulting from increased or
premature destruction of circulating erythrocytes - Types of hemolysis
- Extravascular – destruction by fixed tissue
macrophages (spleen) - Intravascular – destruction while in general
circulation
Extravascular Hemolysis
Extravascular – destruction by fixed tissue
macrophages (spleen)
Intravascular Hemolysis
Intravascular – destruction while in general circulation
Hemolysis – Laboratory Features
- Reticulocytosis (polychromasia)
- Increased serum lactate dehydrogenase
- Increased serum total/unconjugated (indirect)
bilirubin - Decreased serum haptoglobin (intravascular)
- Hemoglobinemia (intravascular)
- Hemoglobinuria (intravascular)
- More specific tests
Hemolytic Anemia - Classification
- Membrane/cytoskeletal defect
- Enzyme defect
- Hemoglobinopathy
- Immune-mediated hemolysis
- Mechanical destruction
- Miscellaneous causes (complement sensitivity,
hypersplenism, burns, parasites)
Hemolytic Anemias (Membrane/cytoskeletal defects:)
- Membrane/cytoskeletal defects:
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Hereditary pyropoikilocytosis
- Acanthocytosis
Hereditary Spherocytosis (Membrane/cytoskeletal defects)
- Inherited (autosomal dominant)
- Deficiency (quantitative) of a cytoskeleton protein
(spectrin) - Vertical defect between cytoskeleton and lipid bilayer
- Progressive loss of membrane with formation of
spherocytes - Extravascular hemolysis
Hereditary Spherocytosis (Membrane/cytoskeletal defects) – Lab Features
- Normocytic anemia with reticulocytosis
- Increased MCHC
- hyperchromic spherocytes/polychromasia on blood smear
- Increased bilirubin (indirect)
- Increased lactate dehydrogenase (mild)
- Increased osmotic fragility
- Erythroid hyperplasia (bone marrow)
Hereditary Spherocytosis (Membrane/cytoskeletal defects) - Clinical
- Moderate anemia
- Transfusion usually not necessary
- Splenomegaly (increased workload)
- Jaundice (bilirubin)
- Cholelithiasis (pigmented gallstones from bilirubin)
- Splenectomy in some patients
Hereditary Elliptocytosis (Membrane/cytoskeletal defects)
- Inherited (autosomal dominant)
- Defect (qualitative) in a cytoskeleton protein
(spectrin) - Horizontal defect within the cytoskeleton (no loss of
membrane) - Elliptical/oval erythrocytes (elliptocytes)
- Extravascular hemolysis (mild)
Hereditary Elliptocytosis (Membrane/cytoskeletal defects) – Lab Features
- Normocytic anemia with reticulocytosis (mild)
- Elliptocytes/ovalocytes on blood smear
Hereditary Elliptocytosis (Membrane/cytoskeletal defects) - Clinical
- Asymptomatic or mild anemia (variable)
- Generally milder than hereditary spherocytosis
Hereditary Pyropoikilocytosis (Membrane/cytoskeletal defects)
- Inherited (autosomal dominant)
- Defect (qualitative) in a cytoskeleton protein (often
doubly heterozygous for two different mutations) - Thermal instability (erythrocytes fragment at lower
temperatures) - Marked anisopoikilocytosis (similar to thermal burn)
- Anemia most severe in childhood
Acanthocytosis (Membrane/cytoskeletal defects)
- Acquired (liver disease) or inherited
(abetalipoprotenemia) - Excess cholesterol in outer leaflet of plasma
membrane - Increased membrane rigidity (spike-like projections)
- Extravascular hemolysis (mild)
Acanthocytosis (Membrane/cytoskeletal defects) – Lab Features
- Normocytic anemia and reticulocytosis (mild)
- Acanthocytes (spur cells) on blood smear
- Hyperchromic (no central pallor) with irregular
spiky projections
Hemolytic Anemias (enzyme defects)
- Enzyme defects
- Glucose-6-phosphate dehydrogenase (G6PD)
deficiency - Pyruvate kinase deficiency
G6PD Deficiency (hemolytic anemia - enzyme defect)
G6PD Deficiency
* Inherited (X-linked recessive)
- Hexose monophosphate shunt
- Decreased reduced glutathione, susceptibility to
oxidative stress - Hemoglobin (Fe2+) oxidized to methemoglobin (Fe3+)
- Extravascular hemolysis
G6PD Deficiency (hemolytic anemia - enzyme defect) – Lab Features
- Episodic normocytic anemia with reticulocytosis
- Heinz body formation
- Bite cells/polychromasia on blood smear
G6PD Deficiency (hemolytic anemia - enzyme defect) - Clinical
- Males express the disease, females are carriers
- Episodic hemolysis following oxidative stress (drugs,
infections) - A(-) variant
– 10-15% of African-Americans - Unstable molecule (10% activity)
- Mediterranean variant
- Essentially absent enzyme activity
- More severe hemolysis
- Favism
Pyruvate Kinase Deficiency (hemolytic anemia - enzyme defect)
- Inherited (autosomal recessive)
- Conversion of phosphoenolpyruvate to pyruvate
- Decreased ATP generation
- Failure of membrane pumps, K+ loss (hypotonicity)
with water loss - Extravascular hemolysis
PK Deficiency (hemolytic anemia - enzyme defect) – Lab Features
- Normocytic anemia with reticulocytosis (variable)
- Echinocytes/polychromasia on blood smear
Hemolytic Anemias - Hemoglobinopathies
- Hemoglobinopathies
- Hemoglobin S
- Hemoglobin C
- Hemoglobin E
- Methemoglobin
Hemolytic Anemias - Immune (antibody)-mediated hemolysis
- Immune (antibody)-mediated hemolysis
- Warm autoantibody
- Cold autoantibody (cold agglutinin)
- Paroxysmal cold hemoglobinuria (PCH)
- Transfusion reactions (immediate/delayed)
- Hemolytic disease of the newborn (HDN)
Warm antibody AIHA: Immune (antibody)-mediated hemolysis
- Antibodies that bind at warm temperatures (37oC)
- IgG, bind to global Rh proteins
- Do not fix complement
- Progressive loss of membrane with spherocyte
formation - Extravascular hemolysis (most often)
Warm-Antibody AIHA: Immune (antibody)-mediated hemolysis – Lab Features
- Normocytic anemia with reticulocytosis
- Spherocytes/polychromasia on blood smear
- Positive direct antiglobulin (Coombs) test
Warm-Antibody AIHA: Immune (antibody)-mediated hemolysis - Clinical
- 80% of AIHA (women > men)
- Causes
- Idiopathic
- Infections (viruses, mycoplasma)
- Collagen vascular disease (SLE)
- Lymphoproliferative disease (CLL)
- Drug-induced
- Treatment with immunosuppression, transfusions,
splenectomy (refractory)
Cold-Antibody AIHA (Cold Agglutinins): Immune (antibody)-mediated hemolysis
- Antibodies that bind at cold temperatures (4oC)
- IgM, bind to i/I antigens
- May fix complement
- Red cell agglutination peripherally, occasionally
intravascular hemolysis - Extravascular hemolysis (liver, spleen)
Cold-Antibody AIHA: Immune (antibody)-mediated hemolysis – Lab Features
- Variable anemia
- Interference with CBC parameters (RBC, MCV, HCT,
MCH, MCHC) – warm the blood sample - Red cell agglutination on blood smear
- Positive direct antiglobulin test (only complement)
- Occasionally evidence of intravascular hemolysis
Cold-Antibody AIHA: Immune (antibody)-mediated hemolysis - Clinical
- Peripheral vaso-occlusion (Raynaud phenomenon)
- Causes
- Idiopathic
- Infections (EBV, mycoplasma)
- Collagen vascular disease (SLE)
- Lymphoproliferative disease
- Drug-induced
- Cold avoidance, immunosuppression/transfusion for
more severe anemia
Paroxysmal Cold Hemoglobinuria (PCH): Immune (antibody)-mediated hemolysis
- Biphasic antibody (Donath-Landsteiner), binds in cold
and activates complement upon warming - IgG, bind to P antigens
- Fixes/activates complement
- Intravascular hemolysis
Paroxysmal Cold Hemoglobinuria (PCH): Immune (antibody)-mediated hemolysis - Lab/Clinical Features
- Severe anemia with reticulocytosis
- No agglutination (IgG)
- Decreased haptoglobin with hemoglobinemia and
hemoglobinuria - Positive direct antiglobulin test (only complement)
- Associated with viral infections, syphilis
- Cold avoidance, transfusions
Hemolytic Anemias - Mechanical trauma
- Mechanical trauma – turbulent flow blood/increased
sheer stress causes red cell fragmentation
(intravascular hemolysis) - Macroangiopathic (larger vessel)
- Prosthetic heart valve, vascular graft, vigorous
exercise, malignant hypertension, vasculitis - Microangiopathic (capillary)
- Microcirculatory thrombosis by platelets/fibrin
(DIC, TTP, HUS)
Hemolytic Anemias: Mechanical Trauma - Lab features
- Variable anemia with reticulocytosis
- Schistocytes on blood smear
- Decreased haptoglobin
- Thrombocytopenia (DIC, TTP, HUS)
- Coagulation abnormalities (DIC only)
Hemolytic Anemias - Miscellaneous causes
- Miscellaneous causes
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Hypersplenism
- Thermal burns
- Erythrocytic parasites (malaria, babesiosis)
Anemia of Chronic Renal Disease
- Decreased erythropoietin synthesis
- Normochromic, normocytic anemia
- Low reticulocyte count
- Recombinant erythropoietin for treatment
- Renal transplant, if feasible, to correct underlying
kidney disease
Pure Red Cell Aplasia
- Selective suppression of erythropoiesis
- Causes
- Parvovirus B19 infection (aplastic crisis)
- Thymic lesions (thymoma, thymic hyperplasia)
- Diamond-Blackfan syndrome (congenital)
- Transient erythroblastopenia of childhood
- Normocytic, normochromic anemia
- Low reticulocyte count
Myelophthisic Anemia
- Bone marrow replacement by an infiltrating process
- Disruption of bone marrow-blood barrier
- Causes
- Myelofibrosis
- Primary or metastatic malignancy
- Granulomatous disease
- Extramedullary hematopoiesis (spleen, liver)
Myelophthisic Anemia Morphology
- Normocytic, normochromic anemia
- Low reticulocyte count
- Leukoerythroblastosis (circulating nucleated red cells
and immature granulocytes) - Teardrop cells
Acute Blood Loss Anemia
- Sudden disruption of vascular integrity
- Blood loss greater than ability of bone marrow to
compensate - Degree of anemia may not initially be apparent (loss
of whole blood) - May require transfusion support
- One unit of red cells should raise hematocrit by 3%
and hemoglobin by 1g/dl
Chemotherapy
general term for any treatment involving the use of chemical agents to treat several diseases
including cancer, viral, microbial and parasitic infections
1971 National Cancer Act
Pres. Richard Nixon
Find a cure for cancer by 1976
$1.6 billion dollars
Purpose of Cancer Chemotherapy (CCT)
- Primary induction CCT
* Drugs given as primary treatment in patients with advanced cancer and no alternative treatment
options
Goals: Palliation: Relieve tumor related symptoms, improve QOL, delay tumor progression.
Curative: Elimination of all known tumor mass. Eliminate small subset of diseases
- Adjuvant CCT
* Drugs given with/after primary therapy, when primary therapy is less than completely effective
* Goals: reduce incidence of local and systemic recurrence, improve survival - Neoadjuvant CCT
* Chemotherapy offered prior other primary treatment (e.g. prior to surgery).
Tumor growth curve in relation to chemotherapy
Gompertzian Model
- The initial description of hematological tumors
described that leukemias and lymphomas tumor
grew exponentially (blue curve) - Studies using mathematical models suggested that
most solid tumors growth using different kinetics but
rather using a Gompertzian model of tumor growth
(red curve). - The Gompertz curve or function, is a type of
mathematical model for a time series. It is a sigmoid
function which describes growth as being slowest at
the start and end of a given time period.
1. Initially, at #1, the tumor grows exponentially until crossing the inflection point (at #2).
2. After #2 whereupon its growth decelerates.
3. As the tumor grows its core lacks oxygen and becomes necrotic. When the rate of growth equals the rate of death
(necrosis) tumor size remains (at 3)
Growth Fraction
- Growth fraction model suggests that tumors consist of pools of
both proliferating and non-proliferating cells - Growth rate depends on the growth fraction (GF), which is the
percent of proliferating cells within a given system - In Burkitt’s lymphoma nearly 100% of the neoplastic cells are
actively undergoing division concurrently, rendering them
highly responsive to cytotoxic chemotherapy. - In colon carcinoma, the growth fraction is less than 5% of cells,
leading to its comparatively diminished sensitivity to
chemotherapy. - However, metastases originating from colon carcinoma and
deposited in organs like the liver initially exhibit a high
growth fraction, making them more susceptible to
cytotoxic anticancer drugs.
CCT and the Cell Cycle
- The cell cycle is susceptible to the effects of both cell cycle-specific
and non-cell cycle-specific cytotoxic anticancer drugs. - Tumor cells, whether normal or neoplastic, display heightened
responsiveness to specific drugs during particular phases, such as
vinca alkaloids affecting mitosis in the M-phase. - Conversely, cell cycle nonspecific drugs (alkylating agents)
influence tumor cells during both active cycling and the resting
phase (G0). - Cell cycle-specific cytotoxic drugs, like antimetabolites, are effective
only when cells are in the appropriate phase during treatment. - Non-cell cycle-specific drugs, including alkylating agents, disrupt
DNA structure through a ‘hit-and-run’ mechanism, with the timing
of cell exposure being less critical, as the drug’s impact becomes
apparent when cells initiate division
Therapeutic index
Therapeutic index is the ratio between drug concentration or dose causing toxicity versus therapeutic effect.
Narrow Therapeutic Index Drugs of CCT Drugs
Most cancer drugs have a “narrow” therapeutic index.
Therapeutic Index: Dose Limiting Toxicity (DLT)
DLT: Describes side effects of a drug or other treatment that are serious enough to prevent an increase in
dose or level of that treatment.
Bone Marrow Suppression (myelosuppression) following therapy is a common DLT for many CCT drugs
Therapeutic Index: Drug Adverse Effects
Bone Marrow (rapid turnover)
* Myelosuppression is a serious consequence of of CCT leading to severe neutropenia, thrombocytopenia, and
sometimes anemia.
* These hematological consequences may restrict the drug dosage that an individual can tolerate.
* They can produce high risk of both infection (neutropenic sepsis) and hemorrhage
Gastrointestinal Tract (rapid turnover)
* CCT drugs may induce anorexia, mucosal ulceration (oral mucositis), or diarrhea.
* Symptoms may include nausea, vomiting, diarrhea, and loss of appetite.
* Use of alkylating drugs and cisplatin can limit an individual’s ability to tolerate an optimal dosage regimen
Reproductive Organs
* Several CCT drugs have teratogenic activity due to their mechanisms of action.
* Pregnant patients should avoid exposure to CCT drugs for treatment or as members of the healthcare team.
* They can produce male infertility and/or adverse effects on sexual function.
Peripheral Neuropathy
* Pain, tingling, numbness, and cold sensations may occur in the hands and feet due to sensory nerve damage,
with effects on motor and autonomic nerves also possible.
* CCT Drugs producing are (some): vinca alkaloids (vincristine), platinum compounds, etc.
Killing Cancer Cells: Log Kill Hypothesis (Classical View)
A given dose/unit time of chemotherapy will kill a constant percentage of cells, not a constant number).
– Same dose is needed to decrease the tumor burden from 10^6 to 10^3 cells as from 10^3 to 10^0 cells.
Log Cell Kill Hypothesis: An Example
“Classic View” Each exposure to a useful cancer drug treatment kills a constant fraction of
“susceptible” cells until all cancer cells are killed OR remaining cells are “dormant” OR are
eliminated by the immune system
B. 6
Cancer Chemotherapy Resistance
- Primary resistance
- Absence of response on initial exposure
- Acquired resistance
- Develops during treatment in response to drug exposure
- Can be highly specific to a single drug
- Some of these responses are mediated by Multidrug resistance (MDR) mechanisms and MDR genes
such as: - MDR1 (ABCB1): This gene encodes P-glycoprotein (P-gp), which is a major player in drug efflux.
Overexpression of MDR1 can lead to decreased intracellular drug concentrations and contribute to
multidrug resistance. - MRP (ABCC) Family: The Multidrug Resistance-Associated Protein (MRP) family includes several
genes (e.g., MRP1, MRP2, MRP3) that encode transport proteins involved in drug efflux. These
proteins contribute to the resistance against a variety of anticancer drugs. - BCRP (ABCG2):Breast Cancer Resistance Protein (BCRP) is encoded by the ABCG2 gene. It acts as a
drug efflux pump and is associated with resistance to certain chemotherapeutic agents.
Six Mechanisms of Drug Resistance in CCT
(C) Increased expression of a P-glycoprotein transporter
Major Classes of CCT Drugs
Alkylating Agents (most of these drugs are CCNS i.e. cell cycle non-specific)
There are different types of alkylating agents based on the chemical structures:
- Nitrogen mustards: cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamustine,
mechlorethamine - Nitrosoureas: streptozocin, carmustine (BCNU), lomustine (CCNU)
- Platinum agents: cisplatin, carboplatin, oxaliplatin
- Alkyl sulfonate: busulfan
- Ethylenimine: Triethylenethiophosphoramide (thiotepa), altretamine
- DNA-methylating drugs/Triazine: Procarbazine (?), dacarbazine, temozolomide. The main mechanism
of action would include generation of H2O2 and oxygen free radicals that cause DNA strand scission.
Most of these alkylating agents are metabolized hepatically and excreted in the urine; dose adjustment
for renal dysfunction and severe hepatic dysfunction is often required.
Nitrogen mustards (Alkylating Agents)
- Major site of alkylation is N7 position of guanine
- Bind to and cross link DNA (single strand or double strand breaks)
- Not cell cycle specific (most susceptible in G1 and S phases)
Alkylating Agents
Nitrogen mustards (Alkylating Agents): Cyclophosphamide
What about the doses clinically used for these drugs? (Alkylating Agents)
(do not memorize the doses)
Cisplatin (Alkylating Agents): Intra- and Interstrand formation
Alkylating Agents - Resistance
- Develops rapidly when given as single agents
- Mechanisms
- Increased capability to repair DNA damage
- Decreased transport of alkylating agents into cell
- Increased activity of glutathione - needed to conjugate alkylating agent
- Increased Glutathione S-transferase, which catalyzes the inactivation of alkylating
agents.
Please note that both elevated glutathione levels and increased activity of the enzyme
glutathione S-transferase have been associated with the resistance of cells to alkylating
agents.
C. Oxaliplatin
Major Classes of CCT Drugs: Antimetabolites
Antimetabolites
Methotrexate (Antimetabolites)
- Folic acid is an essential nutrient, which acts as a supplier of methyl groups to synthesize purines,
pyrimidines, and certain amino acids. When able to donate methyl groups, folic acid exists as a reduced,
methylene folate known as “5,10-methylenetetrahydrofolate” (Me-THF). - Trade Names: Rheumatrex, Methotrex (MTX), Trexall ®
- Drug Class: Antimetabolite / Immunosuppressant / Antineoplastic
- Dose: The oral dose is 7.5 to 20 mg once weekly.
- Contraindications:
– Methotrexate can cause fetal death or teratogenic effects when administered to pregnant patients.
– Methotrexate is contraindicated in patients with hepatic damage
Anti-Metabolite of Folic Acid: Methotrexate - cell cycle specificity and MOA
- Methotrexate (MTX) (MOA)
- Folic acid analog that binds to catalytic site of
dihydrofolate reductase (DHFR) -> inhibits
synthesis of tetrahydrofolate (THF, FH4), a cofactor
needed for synthesis of precursors for DNA, RNA,
and de novo DNA synthesis - S - phase specific activity
- Analogs used are:
– Pemetrexed (PMX)
– Pralatrexate (PTX)
Anti-Metabolite of Folic Acid: Methotrexate - ADE and supportive care
The primary toxicities are:
- Bone marrow suppression
- Intestinal epithelium (mucositis, stomatitis)
The supportive care for high dose MTX include:
* Hydration (during infusion and 48 hours
after)
* Urine alkalinization (i.e. sodium bicarbonate
to maintain urinary pH >7)
* Leucovorin (folinic acid) serves as “rescue
agent” in methotrexate therapy.
* Leucovorin is a reduced form of folic acid,
and it bypasses the blocked enzyme
(dihydrofolate reductase) targeted by
methotrexate.
Antimetabolite: Folic Acid Analog (methotrexate) Resistance
- Decreased methotrexate transport into cells
- Decreased ability to synthesize methotrexate polyglutamylates
- Production of altered forms of DHFR that have decreased affinity for methotrexate
- Increased levels of target enzyme DHFR through gene amplification or altered gene
regulation - Increased expression of a drug efflux transporter of the MRP class (P-Glycoproteins)
C. Leucovorin
Antimetabolites - Purines: Mercaptopurine and 6 Thioguanine
Purines: Mercaptopurine and 6 Thioguanine
- Azathioprine (AZA) is a prodrug of mercaptopurine (MP).
* Thioguanine (TG) and MP can be converted by
hypoxanthine phosphoribosyl transferase (HPRT or
HGPRT) to thioguanine nucleotide (TGNs) metabolites.
* TGN metabolites are incorporated into DNA and RNA
leading to cell death. However, DNA incorporation is
believed to be the primary mode of cytotoxicty
- MP can also be converted to the methyl-thioinosine
monophosphate (meTIMP) by thiopurine
methyltransferase (Tpmt) which inhibits purine
synthesis. - The neoplastic cell become resistant by blocking its
activation by HPRT
Antimetabolites - Cytosine arabinoside (Cytarabine) - MOA (basic) and ADE
- Pyrimidine analog used in AML
- MOA
- Converted to mono-, di-, and triphosphate metabolites
- Triphosphate metabolite competitively inhibits DNA
polymerase α and β -> blocking DNA synthesis and repair - Also incorporated into DNA -> interferes with chain
elongation and defective ligation of newly
synthesized DNA fragments
Cytosine arabinoside (Cytarabine) - Primary toxicities: myelosuppression, mucositis, nausea, vomiting
Antimetabolites - Cytosine arabinoside (Cytarabine) - MOA (advanced)
- Cytarabine is an antimetabolic agent and blocks the
function of DNA polymerase. - Pyrimidine analog used in AML
- After cellular uptake, cytarabine is converted to
cytarabine-5 ́-triphosphate, which is the active
metabolite incorporated into DNA during DNA synthesis. - This results in a cell cycle arrest in the S phase.
Summary Pyrimidine and Purine Analogs
Antimetabolites - 5-Fluorouracil (5-FU)
- 5-Fluorouracil (5-FU) undergoes cellular conversion to 5-
fluoro-2’-deoxyuridine-5’-monophosphate (5-FdUMP). - 5-FdUMP inhibits thymidylate synthase in cells.
- The incorporation of 5-FdUMP into DNA hinders DNA
synthesis and functionality - 5-FU also produces ananother metabolite, 5-
fluorouridine-5’-triphosphate (FUTP). - FUTP disrupts RNA processing and function.
- Resistance mechanisms in tumor cells include :
- Decreased sensitivity of this enzyme to the drug.
5-Fluorouracil (5-FU)
* Toxicity: Severe Bone marrow suppression
Major Classes of CCT Drugs - Topoisomerase Inhibitors
Topoisomerases:
* Topoisomerase I and II are enzymes needed for DNA
replication and cell division.
* They create temporary nicks in DNA to relieve torsional
strain, allowing the DNA to untangle so replication
machinery can access the genome.
* Topoisomerase I cuts one strand of DNA, Topoisomerase II
cuts two strands of DNA
* These enzymes reseal DNA strands after replication.
* Topoisomerase activity is increased in cancer cells.
Topoisomerase Inhibitors:
* In the United States, approved topoisomerase inhibiting
chemotherapeutics include irinotecan and topotecan (topoisomerase I inhibitors) and etoposide and teniposide (topoisomerase II inhibitors).
* They are given intravenously in 3-4 week cycles combined with other agents.
* Major dose-limiting toxicities are myelosuppression and GI issues like diarrhea and nausea.
Topoisomerase Inhibitors (drugs)
Major Classes of CCT Drugs - Antitumor Antibiotics or Antineoplastic Antibiotics
This category of antineoplastic drugs is made up of several structurally dissimilar microbial products
and includes these3 drugs that belong to two main groups:
1. Doxorubicin (Anthracyclines)
2. Bleomycin (Non- Anthracyclines)
3. Mitomycin (Non- Anthracyclines)
Antitumor Antibiotics: Anthracyclines
(Doxorubicin)
* They intercalate between DNA base pairs, inhibit
topoisomerase II, and generate free radicals.
** They block the synthesis of RNA and DNA and
cause DNA strand scission.**
* Membrane disruption also occurs.
- Toxicity is myelosuppression and cardiotoxicity
- Cardiotoxicity: including acute transient ECG
changes (reversible) and chronic cardiomyopathy
leading to the development of heart failure.
Cardiotoxicity develops slowly ( typically becomes symptomatic 5-15 years after therapy is completed)
Antitumor Antibiotics: Non-Anthracyclines Bleomycin
* Bleomycin, which include bleomycinic acid,
BLMA2, and B2, are a family of glycopeptide
derived antibiotics isolated from the Streptococcus
verticullis species.
* Bleomycin must be given parenterally
* Their mode of action is metal-dependent oxidative
cleavage of DNA and RNA in the presence of oxygen
- They produce early drug resistance
* Pulmonary toxicity is very relevant
The toxicity profile of bleomycin includes
pulmonary dysfunction (pneumonitis, fibrosis),
which develops slowly and is dose limiting
Antitumor Antibiotics: Non-Anthracyclines Mitomycins
* Mitomycins are a class of broad-spectrum
antibiotics that function as alkylating agents.
- They covalently bind to DNA and generate crosslinks
between complementary strands as well as single
strand alkylations. - Activation of mitomycins occurs under acidic
conditions found in tumor tissue. - Mitomycins also produce reactive oxygen species
that contribute to antitumor effects.
* Mitomycin causes severe myelosuppression and is
toxic to the heart, liver, lung, and kidneys.
(A) Bleomycin
Inhibitors of Mitosis
Vinca Alkaloids &Taxanes
Mitosis Inhibitors
Summary of Natural Products Used in Cancer
Topoisomerase Inhibitors, Tumor Antibiotics and Mitosis Inhibitors
(Do not memorize)
Hydroxyurea (Hydroxycarbamide): Inhibition
ribonucleotide diphosphate
reductase
- Antimetabolite. It is specific to impairing DNA synthesis (during S-phase) by inhibiting ribonucleotide
reductase (which converts ribonucleotides to deoxyribonucleotides ) - Ribonucleotide reductase (RNR) is responsible for synthesizing deoxyribonucleotides, which is the sugar
building block of DNA. - Hydroxyurea exploits the sensitivity of highly proliferative myeloproliferative neoplasms and leukemias
given their dependency on abundant deoxyribonucleotide (dNTPs) pools to support brisk cell division rates.
Hormonal Anticancer Agents
*Glucocorticoids (Prednisone,
Dexamethasone, etc)
GLUCOCORTICOIDS (GCs)
Naturally occurring compound is cortisol which is released
by the adrenal gland
- What is their mechanism of action?
- GCs exert their effects either genomically (slow pathway)
or non-genomically (fast pathway). - GCs binds to the cytoplasmic GC Receptor (GR) which
undergoes dissociation from accessory proteins (heat shock proteins (HSPs), and translocate into the nucleus. - In the nucleus, GR activates or represses transcription of genes by directly binding to glucocorticoid-response
elements (GREs) or negative GREs, or by tethering to other transcription factors (TFs) - GCs act via the mitochondrial pathway to cause caspase
activation to promote apoptosis of lymphocytes and
eosinophils
* End result: decrease in cytokine release, including
decreases in IL-2 and TNF α
Glucocorticoids (GC) in Cancer
- GCs are used to induce cell apoptosis in malignant lymphoid cancers, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLLetc
- In non-hematologic malignancy, GCs monotherapy or
combined therapy with other cytotoxic drugs, such as 5-
fluorouracil (5-FU), had shown modest benefit in breast and prostate cancers, but not in other cancer types. - However, the addition of GCs to other therapy does not
change the long-term survival in advanced breast cancer. - Dexamethasone used to reduce edema from tumors in areas like the brain, spinal cord (review in SMS course)
- There are some adverse effects also described in specific tumors. GC may enhance breast and prostate cancer progression.
- GCs are widely accepted as an adjuvant during
chemotherapy or radiotherapy for reducing side effects in many cancer types. Treatment of GCs increases appetite, decreases weight loss, reduces fatigue, etc.
Principles of Combination Chemotherapy
In 1965, Holland et al suggested the use of combination
chemotherapy as the best strategy for cancer chemotherapy.
Cancer cells could mutate to become resistant to a single
agent, but by using different drugs concurrently it would be more difficult for the tumor to develop resistance to the combination.
Requirements for Combination Chemotherapy
1. Each drug should target a different phase in the cell cycle to achieve maximum cell death and reduce
resistance.
2. Each drug should have a different mechanism of action within the cancer cell; this will maximize the chance
of synergistic effects.
3. Each drug should have activity against the cancer when used alone; a second drug would not be given
simply to increase the formation of an active metabolite of the first, although sometimes drugs are given to
reduce the development of toxicity or resistance to another drug.
4. Each drug should have a different toxicity; some common toxicity is almost inevitable because nearly all
these drugs affect tissues with a high growth fraction.
Testicular cancer
most common in young or middle-aged men (15-35 years old). Average diagnosis is 33 years-old
- In fact, testis cancer is the most common malignancy among men 20 to 40 years old (Hopkins)
- About 1 of every 250 males will develop testicular cancer at some point during their lifetime.
- Estimated new cases and deaths (Hopkins): New cases: 8,000-10,000, and Deaths: approx. 400/year
Combination Chemotherapy Protocols in Testicular Cancer (some examples):
VBP: Vinblastine, Bleomycin, Cisplatin
BEP: Bleomycin, Etoposide, Cisplatin
EP: Etoposide and Cisplatin
D) Targeting different phases in the cell cycle and having different mechanisms of action
Chemotherapies: summary
