Nursing Pharmacology: Antimetabolites
Structural analogues: Neoplastic cells' metabolic differences lead to increased susceptibility to actions of antimetabolites.
Most antimetabolites interfere with nucleic acid synthesis or nucleotide synthesis.
Mechanism of Action: Folic acid antagonist: acts at catalytic side of dihydrofolate reductase
Polyglutamate: important in methotrexate action
Tumor resistance to methotrexate:
Decreased drug transport into the cell
Altered dihydrofolate reductase enzyme exhibiting lower affinity for methotrexate
Decreased polyglutamate formation
Quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message)
Adverse effects:
Bone marrow suppression
Dermatologic
GI mucosa
Adverse effects reversed by leucovorin (citrovorum factor)
Leucovorin "rescue" may be used in cases of overdosage or in high-dose methotrexate protocols
Other uses:
Treatment of rheumatoid arthritis
In combination with a prostaglandin: induces abortion
Primary Reference: 1Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911
2Angstadt, C., Purine and Pyrimidine Metabolism