1. OBJECTIVES
To learn the mechanism of cytotoxicity and toxicity of the commonly used antimetabolites

2. 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).

4. 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.

6. 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

8. 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

9. 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

11. 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

12. 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

13. Myelosuppression. Useful in pancreas and lung cancers

15. 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

17. 5-Fluorouracil (2) Leucovorin enhances the cytotoxicity of 5-FU.
5-FDUMP + leucovorin forms a strong inhibitory complex with thymidylate synthesisthymineless 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.

20. 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.

21. 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”.

22. Capecitabine

24. 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

25. Hand-Foot Syndrome

27. 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 % when coadministered with allopurinol

28. 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.