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Activity of the thymidylate synthase inhibitor 2-desamino-N-10- propargyl-5,8-dideazafolic acid and related-compounds in murine (L1210) and human (W1l2) systems in Vitro and in L1210 in Vivo

Lookup NU author(s): Geoffrey Taylor, Professor Alan Calvert


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We examined the in vitro activity of 2-desamino-5,8-dideazafolate and 2-desamino-N10-propargyl-5,8-dideazafolate (desamino-CB3717), the more water-soluble 2-desamino analogues of 5,8-dideazafolate and N10-propargyl-5,8-dideazafolic acid (CB3717). We report Ki values for the inhibition of L1210 thymidylate synthase (TS) of 2 and 0.027 microM for 2-desamino-5,8-dideazafolate and desamino-CB3717, respectively, indicating a 30- and 10-fold loss in TS-inhibitory activity compared with the corresponding 2-NH2 compounds. The synthetic tri- and tetrapolyglutamate derivatives of desamino-CB3717 were 66- and 101-fold more potent than the monoglutamate form as inhibitors of TS. Both desamino compounds were more potent as inhibitors of L1210 and W1L2 cell growth than were their 2-amino counterparts. 2-Desamino-5,8-dideazafolate retains quite good activity against both the TS-overproducing W1L2:C1 line and the L1210 cell line grown in the presence of thymidine, suggesting that a secondary locus of action may be involved. This other target is a folate-dependent enzyme as evidenced by the protection of the inhibition of cell growth by the addition of hypoxanthine or folinic acid together with thymidine. The methotrexate-resistant, dihydrofolate reductase-overproducing L1210:R7A cell line is cross-resistant to 2-desamino-5,8-dideazafolate, which suggests that dihydrofolate reductase is the other target. An L1210 subline (1565) unable to transport reduced folates is 10-fold resistant to desamino-CB3717 and 2-desamino-5,8-dideazafolate but is not cross-resistant to CB3717 or 5,8-dideazafolate. The removal of the 2-amino function of CB3717 did not affect folylpolyglutamate synthetase substrate activity (CB3717 Km = 48 microM, desamino-CB3717 Km = 40 microM). However, both 5,8-dideazafolate and its desamino analogue were about 10-fold better substrates for folylpolyglutamate synthase than were the N10-propargyl compounds, and this may contribute to their good growth-inhibitory properties. In vivo, desamino-CB3717 cured approximately 75% of mice bearing the L1210:ICR tumor at doses of 50 mg/kg daily for 5 days and above (maximum tolerated dose greater than 1000 mg/kg daily for 5 days).(

Publication metadata

Author(s): Jackman AL, Taylor GA, O'Connor BM, Bishop JA, Moran RG, Calvert AH

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 1990

Volume: 50

Issue: 17

Pages: 5212-5218

Print publication date: 01/09/1990

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445


PubMed id: 2386929