Active Transport of Antifolates

Classical antifolates such as methotrexate (MTX, 1), an antifolate agent targeting DHFR, and pemetrexed (Alimta, 2), a multitargeted antifolate, are actively transported into cells by the reduced folate carrier (RFC). Antifolates can also be transported via the membrane folate receptors (MFRs) through either endocytosis or potocytosis.16 The RFC is a high affinity transporter for reduced folate cofactors such as 5-methyl-THF, 5-formyl-THF as well as MTX. Folic acid, on the other hand, is a poor substrate for the RFC. The MFRs are linked to the outer plasma membrane via a glycosylphosphatidylinositol anchor, and have a high affinity for folic acid. The affinity of the MFRs for MTX is about 100-fold less than for folic acid, but other antifolates such as pemetrexed show enhanced affinity over folic acid.

Figure 3 Reversible oxidation of nucleoside diphosphate reductase (NDPR). (Reprinted from Henry, J. R.; Mader, M. M. Recent Advances in Antimetabolite Cancer Chemotherapies. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Elsevier: Oxford, UK, 2004, pp 161-172, with permission from Elsevier.)

Figure 3 Reversible oxidation of nucleoside diphosphate reductase (NDPR). (Reprinted from Henry, J. R.; Mader, M. M. Recent Advances in Antimetabolite Cancer Chemotherapies. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Elsevier: Oxford, UK, 2004, pp 161-172, with permission from Elsevier.)

formation

Defective RFC transport has been recognized as a common mechanism of resistance of cell lines to the effects of antifolate drugs.17 Resistance is manifested as either decreased affinity for drug by RFC, or reduced expression of the RFC. A third mechanism of resistance has also recently been identified wherein an altered RFC exhibits increased affinity for folic acid. The increased level of folic acid in the cell then results in a loss of polyglutamation and therefore activity of the antifolate agent.18

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