© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 14, 1178-1179,
July 21, 1999
© 1999 Oxford University Press
EDITORIALS |
Enhancing Cytotoxic Sensitivity of Tumor Cells to Antifolates: Another Opportunity for Gene Therapy?
Correspondence to: F. M. Sirotnak, Ph.D., Laboratory of Molecular Therapeutics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: sirotnaf@mskcc.org).
Effective cytotoxic action of classical folate analogues against
tumor cells (1,2) relies not only on their potent inhibition
of the primary intracellular target—analogues have been tailored to
inhibit dihydrofolate reductase, thymidylate synthase, and glycinamide
ribonucleotide formyl transferase—but also on their efficiently
mediated internalization and subsequent conversion to
poly-
-glutamates. As with natural folates, internalization of
folate analogues by tumor cells [reviewed in (2)] is
mediated by a plasma membrane transporter encoded by the RFC-1 gene.
The enzymatic conversion of the internalized folate analogue to
poly--glutamates occurs by amide bond formation at the
-carboxyl group of the resident glutamyl moiety of the folate
analogue with the amino group of a second glutamate (1,3). A
series of these reactions, mediated
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