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Clinical Cancer Research Vol. 10, 1080-1089, February 2004
© 2004 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

The Role of {alpha}-Folate Receptor-Mediated Transport in the Antitumor Activity of Antifolate Drugs

Davinder S. Theti and Ann L. Jackman

Section of Medicine and the Cancer Research United Kingdom Centre for Cancer Therapeutics, the Institute of Cancer Research, Sutton, Surrey, United Kingdom

Purpose: Raltitrexed, pemetrexed, lometrexol, and ZD9331 are antifolate drugs transported into cells via the ubiquitously expressed reduced-folate carrier. They display also high affinity for the {alpha}-folate receptor ({alpha}-FR), a low capacity folate transporter that is highly overexpressed in some epithelial tumors. The role of {alpha}-FR in the activity of the antifolates has been evaluated in two {alpha}-FR-overexpressing cell lines grown in a physiological concentration of folate (20 nM R,S-Leucovorin).

Experimental Design and Results: A431-FBP cells (transfected with the {alpha}-FR) were 3–5-fold more sensitive to the antifolates than A431 cells. KB cells (constitutive {alpha}-FR overexpression) were less sensitive to the drugs when coexposed to 1 µM folic acid to competitively inhibit binding to the {alpha}-FR. Raltitrexed, pemetrexed, and lometrexol are polyglutamated in cells leading to drug retention, e.g., the raltitrexed 4- and 24-h IC50s in A431 cells were ~0.6 and 0.008 µM, respectively, compared with 0.003 µM for 72-h continuous exposure. A431-FBP cells were ~3-fold more sensitive to raltitrexed and pemetrexed at all exposure times. ZD9331 is not polyglutamated, and the 4- and 24-h IC50s in A431 cells were >100 and ~100 µM, respectively, reducing to 2 and 0.1 µM, respectively, in A431-FBP cells. The ZD9331 4- and 24-h IC50s in KB cells were 20 and 1 µM, respectively, and reversible by coaddition of 1 µM folic acid. An in situ thymidylate synthase assay demonstrated continued thymidylate synthase inhibition after ZD9331-treated A431-FBP and KB, but not A431, cells were placed in drug-free medium for 16 h. A model is proposed in which the antifolates accumulate in the {alpha}-FR/endosomal apparatus, leading to slow release into the cytoplasm. In particular, this leads to cellular retention of the nonpolyglutamatable ZD9331.

Conclusions: Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the {alpha}-FR.




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