ENHANCEMENT OF ANTI-TUMOR ACTIVITY OF 2,4-DIAMINO-5-(3',4'-DICHLOROPHENYL)-6-METHYLPYRIMIDINE AND BAKERS ANTIFOL (TRIAZINATE) WITH CARBOXYPEPTIDASE-G1

  • 1 January 1979
    • journal article
    • research article
    • Vol. 39  (9) , 3441-3445
Abstract
Carboxypeptidase G1 (CPDG1) [from an unidentified Pseudomonas strain], an enzyme that degrades folates but not the nonclassical folate antagonists triazinate (TZT, Baker''s antifol) and 2,4-diamino-5-(3'',4''-dichlorophenyl)-6-methylpyrimidine (DDMP), enhanced the antineoplastic activity of these antifolates. In 6-day cell culture experiments with rat Walker 256 carcinosarcoma, CPDG1 at levels up to 0.54 unit/ml showed very little inhibitory effect on growth. In the presence of 10-7 M DDMP, the growth of Walker 256 cells was similar to that of controls, but in combination with CPDG1 (0.1 unit/ml) 80R growth inhibition was observed. TZT at a concentration of 10-8 M did not affect the growth of Walker 256 cells. The combination of 10-8 M TZT with CPDG1 (0.1 unit/ml), strongly inhibited cell growth. In experiments with rats bearing Walker 256 carcinosarcoma, the administration of CPDG1 (800 units/kg per day) from day 1 to day 6 resulted in no significant increase in life span. Administration of TZT in doses up to 0.05 mg/kg on Day 1 or that of DDMP up to 15 m/kg on days 1, 3, and 5 had no antitumor effects as measured by survival of the animals. CPDG1 (800 units/kg per day) from day 1 to day 6 in combination with TZT (0.05 mg/kg on day 1) or DDMP (15 mg/kg on days 1, 3, and 5) resulted in increases of 50 and 30%, respectively, in the survival of the tumor-bearing animals. CPDG1 enhances the antitumor effects of TZT or DDMP.

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