Drugs For Colorectal Cancer

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Antimetabolites: Fluorouracil (Leucovorin) and capecitabine
A. Mechanism of action

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These drugs are classified as antimetabolites. They are cell cycle specific for the S phase of the cell cycle.
5FU inhibs thymidylate synthetase
5-FU may be converted to fluorouridine (FUR) by uridine phosphorylase and then to FUMP by uridine kinase,
FUMP can converted to the triphosphate, FUTP, and incorporated into RNA thus inhibiting the processing and function of RNA.
Ultimately, interaxn between FdUMP and thymidylate synthetase blocks the synth of TTP, (a DNA constituent)

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enhanced cytotoxicity--5-FU enhances effect of irradiation

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Capecitabine--mech

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a. Capecitabine is an analog of 5-FU.
b. It is converted to 5´-deoxy-5-fluorocytidine by carboxylesterase activity in liver and other normal and malignant tissues. From that point, it is converted to 5´-deoxy-fluorodeoxyuridine by the cytidine deaminase. The final step in its activation occurs when thymidine phosphorylase cleaves off the 5´-deoxy sugar, leaving intracellular 5-FU.

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Leucovorin

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i. Malignant cells may have insufficient concentrations of 5,10-methylene tetrahydrofolate and cannot form maximal levels of the inhibited ternary complex with thymidylate synthetase.
ii. Addition of exogenous folate in the form of
5-formyl-tetrahydrofolate (leucovorin) increases formation of the complex and enhances the cytotoxicity of 5-FU.

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Oxaliplatin

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i. The effects of 5-FU and oxaliplatin are synergistic.
ii. Oxaliplatin inhibits catabolism of 5-FU to dihydro 5-FU by inhibiting dihydropyrimidine dehydrogenase. Oxaliplatin also may inhibit expression of thymidylate synthetase.

dh5FU is off the normal p'way and is almost a breakdown product of 5FU

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Mechanisms of resistance--5FU

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1. Loss or decreased activity of the enzymes necessary for activation of 5-FU
2. Amplification of thymidylate synthetase
3. Mutation of thymidylate synthetase to a form that is not inhibited by FdUMP

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Administration and elimination
1. 5-FU

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a. 5-FU is administered intravenously
b. Metabolic degradation occurs in many tissues including liver, intestinal mucosa, and tumor cells by reduction by dihydropyrimidine dehydrogenase (DPD) to dihydro 5-FU. Inherited deficiency of this
enzyme leads to greatly increased sensitivity to the drug.
c. No dosage adjustment is necessary in liver disease since the drug is metabolized at other sites.

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Administration and elimination--Capecitabine

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a. Capecitabine is well absorbed orally
b. It is rapidly de-esterified and deaminated, yielding high plasma concentrations of 5´-deoxy-fluorodeoxyuridine (5´-dFdU). The conversion of 5´-dFdU to 5-FU by thymidine phosphorylase occurs in liver, peripheral tissues, and tumors. Liver dysfunction may delay the conversion of the parent compound to 5´-dFdU and 5-FU.

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Adverse reactions--FU's

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1. Myelosuppression
2. Mucositis
3. Diarrhea
4. Palmar-plantar erythrodysesthesia (hand-foot syndrome) consisting of erythema, desquamation, pain, and sensitivity to touch of the palms and soles

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Oxaliplatin
A. Mechanism of action

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1. Oxaliplatin is converted to a positively charged intermediate that binds DNA forming intrastrand cross-links between neighboring guanines. This causes bending of the DNA preventing bases from lining up with each other. Interstrand cross-linking occurs as well.
2. Can damage DNA during any phase of the cell cycle, thus it is not cell cycle specific.

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Mechanism of resistance--Oxaliplatin

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1. Increased intracellular concentrations of nucleophilic substances, e.g., glutathione, which can conjugate and detoxify electrophilic intermediates.
2. Increased activity of DNA repair pathways

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Oxaliplatin--Administration and elimination

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1. Administered intravenously
2. Inactivated in the cells and blood stream by sulfhydryl groups; the drug is excreted in the urine; reduce dose in patients with reduced renal function

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Oxaliplatin--Adverse reactions

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1. Unlike cisplatin, oxaliplatin is not nephrotoxic, ototoxic, or highly emetogenic
2. Anaphylactic reactions including pruritus, rash, and urticaria. Can be managed with epinephrine, corticosteroids, or antihistamines.
3. Peripheral neuropathy
a. Acute form has a rapid onset, reversible, exacerbated by cold, affects hands, feet, perioral area, and throat
b. Persistent form has a later onset (>14 days) and affects mainly hands and feet; may be permanent

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Bevacizumab
1. Mechanism of action

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a. A humanized monoclonal antibody against vascular-endothelial growth factor (VEGF)
b. Inhibits interaction of VEGF with it receptors (VEGFR1 and VEGFR2) thus inhibiting angiogenesis.
c. (VEGF is an angiogenic growth factor that regulates vascular proliferation and permeability and inhibits apoptosis of new blood vessels. VEGF expression is increased in a variety of tumor types itsexpression correlates with neovascularization within tumor masses).

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Bevacizumab--admin

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IV

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Bevacizumab--Adverse reactions

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a. GI bleeding or perforation
b. Hypertension
c. Proteinuria

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Cetuximab
1. Mechanism of action

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a. A chimeric monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR).
b. Inhibition of EGF binding and signaling leads to inhibition of pro-angiogenic factors and apoptosis.
c. (Activation of EGF receptor signaling through tyrosine kinase produces multiple cellular events associated with proliferation, survival, and angiogenesis. EGFR expression is found many patients with colorectal
cancers.)
d. EGFR signal transduction results in K-ras wild-type activation; cells with K-ras mutations are unaffected by EGFR inhibition. K-ras gene mutations downstream of EGFR are present in approximately 35% of patients with metastatic colorectal cancer and are a biomarker for nonresponse to cetuximab, for which reason the use of this drug is restricted to patients with tumors wild-type for K-ras.

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Cetuximab--admin

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IV

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Cetuximab--Adverse Rxns

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a. Infusion reactions (bronchospasm, stridor, hoarseness, urticaria, hypotension)
i. If severe, treatment should be stopped and permanently discontinued
ii. Mild to moderate infusion reactions can be managed by slowing the infusion rate and administering antihistamines
iii. Immediate treatments for anaphylactic reactions should be available
b. Acne-like rash in most patients, sometimes severe, on face and upper torso, onset in 1–3 weeks, may improve with continued treatment,
reversible;

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Irinotecan
A. Mechanism of action

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Topoisomerase inhibitor
1. Irinotecan is a prodrug. It is cleaved by a carboxylesterase in the liver to form the biologically active metabolite known as SN-38 which inhibits topoisomerase I.
2. Irinotecan binds to and stabilizes the DNA-topoisomerase I complex. Although the initial cleavage action of topoisomerase I is not affected, the religation step is inhibited, leading to the accumulation of single-stranded breaks in DNA. Upon collision of a DNA replication fork with this cleaved strand of DNA irreversible double-strand DNA break occur ultimately leading to cell death.
3. Irinotecan is S-phase-specific because ongoing DNA synthesis is
necessary for cytotoxicity.
4. (Topoisomerase I binds covalently to double-stranded DNA through a
reversible trans-esterification reaction. This reaction yields an intermediate
complex in which the tyrosine of the enzyme is bound to the 3´-phosphate
end of the DNA strand, creating a single-strand DNA break. This "cleavable
complex" allows for relaxa

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Irinotecan--Mechanisms of resistance

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1. Enhanced ability to repair DNA strand breaks
2. Mutation or decreased expression of topoisomerase I

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Irinotecan--Administration and elimination

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1. Administered intravenously
2. Metabolism of both irinotecan and SN-38 in the liver

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Irinotecan--Drug interactions

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1. The levels or effects of irinotecan can be decreased by inducers of P450 enzymes (e.g., phenytoin).
2. The levels or effects of irinotecan can be increased by inhibitors of P450 enzyme (e.g., macrolide antibiotics)

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Irinotecan--Adverse reactions

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1. Diarrhea
a. Acute (cramping, flushing, vomiting, diaphoresis within 1 hour of completion) related to increased levels of acetylcholine due to inhibition of acetylcholinesterase by irinotecan; the cholinergic effects can be controlled with atropine.
b. Delayed (>24 hours after administration; usually after the second or third dose); may be severe; can be controlled with loperamide.
2. Myelosuppression

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Summary of clinical uses of these drugs in colorectal cancer

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"You do not need to memorize
these regimens, however."