OBJECTIVES To learn the mechanism of cytotoxicity and toxicity of the commonly used antimetabolites
OVERVIEW: The antimetabolites are structural analogs of naturally occurring metabolites. Therefore, they can substitute for the naturally occurring metabolites in biochemical pathways and cause cessation of synthesis-usually of nucleic acids. The antimetabolites are cell cycle specific (acting during the S-phase).
Methotrexate Cycle specificity: CCS (S phase) Binds to dihydrofolate reductase (DHFR) decreasing tetrahydrofolate (serves as a one carbon donor in purine synthesis). Polyglutamation retards cellular egress of methotrexate and increases the inhibition of enzymes involved in purine and thymine synthesis. Administration of tetrahydrofolate (leucovorin) can rescue the cell from the cytotoxicity of methotrexate if the methotrexate is not polyglutamated.
Methotrexate (2) Nausea, vomiting, stomatitis and myelosuppression Reduce dose in renal insufficiency Approved for intrathecal administration Intravenous or oral Uses: lymphoma, leukemia, brain tumors, breast cancer, rheumatoid arthritis, psoriasis
High dose methotrexate with leucovorin rescue Hydration (saline and bicarbonate IV) and alkalinization of urine. Check urine pH each void (>= 7 to start, if less give additiona sodium bicarbonate) Administer methotrexate Begin intravenous or oral leucovorin rescue. Monitor methotrexate levels Stop rescue when methotrexate level is < 5 X 10-7 M at 48 hours
Pemetrexed Antifol Polyglutamated Main action is inhibition of thymidylate synthase Myelosuppression is dose limiting. Rash, stomatitis, diarrhea and hand foot syndrome Pretreatment with vitamin B-12 and oral folic acid decreases the extent of myelosuppression Lung cancer and mesothelioma
Cytosine arabinoside Cell cycle specific (S-phase) pyrimidine analog Undergoes sequential phosphorylation to the triphosphate and is incorporated into DNA. Inhibits DNA polymerase and chain elongation Myelosuppression, nausea and vomiting, hair loss, stomatitis and hepatic toxicity
Cytosine arabinoside Used in treatment of leukemia Short half-life and cell cycle sepcificity Schedule dependent cytotoxicity 3 +7 regimen for acute myelogenous leukemia induction: 3 days of intravenous administration of an anthracycline and 7 days of continuous infusion of cytosine arabinoside (168 hours) High dose cytosine arabinoside therapy Myelosuppression, cerebellar toxicity, conjunctivitis Approved for intrathecal administration
Myelosuppression. Useful in pancreas and lung cancers
5-Fluorouracil Cell cycle specific, S-phase Nausea, vomiting, stomatitis, rash, diarrhea and myelosuppression. Hyperpigmentation of the skin of the palms of the hands. Increased sensitivity to sunlight. Rarely, coronary artery vasospasm and cerebellar toxicity. Excess lacrimation and hand-foot syndrome
5-Fluorouracil (2) Leucovorin enhances the cytotoxicity of 5-FU. 5-FDUMP + leucovorin forms a strong inhibitory complex with thymidylate synthesisthymineless death. Response rates are higher when coadministered with leucovorin. Leucovorin enhances the cytotoxicity of 5-FU and diminishes the toxicity and cytotoxicity of methotrexate. Gastrointestinal toxicity is also enhanced.
5-Fluorouracil (3) 5-FU is 80 % metabolized in the liver. Initial enzyme is dihydropyrimidine dehydrogenase (DPD). Enzyme is involved in metabolism of uracil and thymine Autosomal recessive, testing is available Severe toxicity when these patients are given 5- FU (severe myelosuppression and diarrhea and stomatitis.
5-Fluorouracil (4) There are different schedules of administration and the toxicity profiles differ depending on the schedule of administration Uses: breast, head and neck and gastrointestinal malignancies Frequently given concomitantly with radiation therapy as a “radiation sensitizer”.
Capecitabine
Capecitabine 1250 mg/M^2 PO Q 12 hours for 14 days every 21 days. Rash, diarrhea, stomatitis, hand-foot syndrome, some myelosuppression Can substitute for intravenous infusions of 5-FU Oral administration Copay of varying amount required
Hand-Foot Syndrome
6-Mercaptopurine (2) Cell cycle specific, S-phase Metabolized by enzymes to 6-thioinosinic acid which inhibits enzymes needed for purine nucleotide synthesis Metabolized to inactive 6-thiouric acid by xanthine oxidase which is inhibited by allopurinol Dose reduce 6-mercaptopurine 50-75 % when coadministered with allopurinol
6-Mercaptopurine Myelosuppression is dose limiting Used to treat childhood leukemia Other drugs: 6-thioguanine can be used at full dose when the patient is also receiving allopurinol because 6-thioguanine undergoes deamination that does not involve the enzyme xanthine oxidase.