Unresolved issues in the biochemical pharmacology of antifolates.
Despite extensive knowledge of the molecular basis for anticancer selectivity of antifolates, particularly classical antifolates, several fundamental questions remain unanswered. It is still not known why antifolate-treated cells die, rather than remain in stasis. The role of uracil misincorporation into DNA in causing irreparable damage has not yet been completely clarified, nor to what extent the antipurine effect of methotrexate (MTX) may be a desirable effect that contributes to antitumor activity. The antipurine effect may cause progression delay, with paradoxical "self-antagonism"; possibly the antipurine effect of MTX is a cause of toxic side effects. Even less is known about the molecular pharmacology of nonclassical antifolates. If they are not dependent for cellular uptake upon a neoplastic transformation-linked carrier, and since they are not subject to polyglutamylation, the molecular basis for anticancer selectivity of nonclassical antifols is unclear. The mechanism by which trimetrexate and metoprine are transported into cells is not known; if it is by passive diffusion, it is odd that resistance is sometimes associated with impaired drug uptake. Other unanswered questions are the mechanism of cross-resistance of doxorubicin-resistant cells to trimetrexate, and why the cytotoxic effect of trimetrexate, at low concentrations, is reversed by thymidine in the absence of purines. Questions also remain concerning antifolate inhibitors of thymidylate synthase (TS), such as how 5,8-dideaza-10-propargylfolic acid (CB3717) enters cells, and whether TS inhibitors will have activity against slowly growing tumors. These and related questions are discussed in relation to the design of optimal antifolate chemotherapy.
Jackson
R C
RC
Chemotherapy Department, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105.
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D011687:Purines / Q000037:antagonists & inhibitors; D012995:Solubility; D013938:Thymidine Monophosphate / Q000037:antagonists & inhibitors; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000477:Alkylating Agents; D005493:Folic Acid Antagonists; D011687:Purines; D013938:Thymidine Monophosphate; D013940:Thymidylate Synthase