Method for Increasing Efficacy of Anti-Folates
Anti-folates are antagonists of the action of the folate family of essential human vitamins, all of which are derived from the folic acid structure. The most commonly used antifolate in humans is currently methotrexate (MTX). MTX is used to treat a number of pathological conditions, including cancer, rheumatoid arthritis, psoriasis, and graft- versus-host disease following bone marrow transplantation. Newer anti-folates are currently only approved to treat specific cancers (colon and mesothelioma). Anti-folates that closely resemble the folates structurally and which include single glutamate (Glu) moiety that occurs in folates are termed “classical” anti-folates. Classical antifolates are primarily transported into human cells by the equilibrative reduced folate carrier (RFC). Transport by tumors can be limiting to the therapeutic effect of antifolates. It has been found that conditions that selectively increase antifolate uptake and/or metabolism into target cells should increase the therapeutic index of the antifolate.
There are currently no known compounds that potentiate the uptake and metabolism of antifolates via increased activity of the RFC. Likewise, there are no compounds that increase synthesis of antifolate polyglutamates.
Researchers at Roswell Park Comprehensive Cancer Center have shown that exogenous 5-amino-4-imidazolecarboxamide riboside (Z) or its nucleobase would affect mammalian folate metabolism. Z also enhances the growth inhibitory potency of MTX against leukemia cells when given concurrently in short-term exposure. Researchers have also shown that Z does not decrease MTX efflux and that administration of Z with an antifolate could lead to increased therapeutic efficacy. Although this potentiating effect has been tested only in tumor cells, it may also occur in the target cells in other pathological conditions such as rheumatoid arthritis and psoriasis.