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Drug Development Section, Institute of Cancer Research, 15, Cotswold Road, Belmont, Sutton, Surrey, SM2 5PX [A. L. J., G. A. T., W. G., R. K., M. B., A. H. C., I. R. J.], and ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, SK10 4TG [L. R. H.], United Kingdom
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is a water-soluble, folate-based thymidylate synthase (TS) inhibitor designed to be a less toxic and more potent analogue of the clinically tested N10-propargyl-5,8-dideazafolic acid. Inhibition of isolated L1210 TS by ICI D1694 is mixed noncompetitive (although tending toward competitive), with a Ki of 62 nM (Kles = 960 nM). The synthetic 
-polyglutamates are up to 2 orders of magnitude more potent as inhibitors of TS; e.g., the tetraglutamate (glu4) has a Ki of 1.0 nM (Kles = 15 nM). Although inhibitory activity of ICI D1694 toward rat liver dihydrofolate reductase was similar to that of TS (Ki = 92 nM; competitive inhibition) the polyglutamate derivatives did not show enhanced activity. ICI D1694 was also a very potent inhibitor of L1210 cell growth (50% inhibitory activity = 8 nM). L1210 growth inhibition was not observed in the presence of thymidine, consistent with TS being the locus of action. Folinic acid antagonized L1210 growth inhibition in a competitive fashion such that the highest folinic acid concentration used (25 µM) increased the 50% inhibitory activity 6000-fold. When given as a 4-h delayed "rescue", folinic acid was much less effective in antagonizing growth inhibition. These observations are consistent with folinic acid competing with ICI D1694 for uptake into the cell and/or intracellular polyglutamation. The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694 (121-fold), suggesting that ICI D1694 is dependent on this uptake mechanism for good cytotoxic potency in L1210 cells. L1210 cells that were incubated for 4 h with 0.1 µM 3H-ICI D1694 accumulated 
1.5 µM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4). Upon resuspension in drug-free medium for 24 h, 75% of the cellular 3H was retained, this being the higher polyglutamate pool (glu4–6). In mice, after a single bolus injection of 10 mg/kg of ICI D1694, TS was inhibited >80% for 24 h in ascitic L1210:NCI cells (as measured by the rate of 3H release from [5-3H]deoxyuridine). ICI D1694 cured the L1210:ICr ascitic tumor in mice at 0.4 mg/kg daily for 5 days (maximum tolerated dose, 50 mg/kg). This antitumor activity was prevented by coadministration of thymidine, indicating that TS is the sole locus of action in vivo. Coadministration of folinic acid (20 mg/kg) with five daily injections of 10-mg/kg ICI D1694 also resulted in ablation of the antitumor activity. We conclude from the presented evidence that rapid cellular uptake of ICI D1694 and retention as more active polyglutamate metabolites are responsible for its excellent antitumor potency both in vitro and in vivo.
1 This work was supported by a grant to the Institute of Cancer Research: Royal Cancer Hospital from the Cancer Research Campaign and The Medical Research Council.
2 To whom requests for reprints should be addressed, at Institute of Cancer Research, Drug Development Section, Block E, 15 Cotswold Road, Relmont, Sutton, Surrey SM2 5NG, United Kingdom.
3 Present address: Cancer Research Unit, Medical School, University of Newcastle, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, United Kingdom.
Received 4/25/91. Accepted 8/ 8/91.
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