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Enhancement of Antitumor Activity of 2,4-Diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine and Baker's Antifol (Triazinate) with Carboxypeptidase G₁¹

Department of Pharmacology [J. R. B., B. A. M.], School of Medicine, and Department of Engineering and Applied Science [C. H., K. K. K.], Yale University, New Haven, Connecticut 06520

Carboxypeptidase G₁ (CPDG₁), 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 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) 80% 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), however, strongly inhibited cell growth. In experiments with rats bearing Walker 256 carcinosarcoma, the administration of CPDG₁ (800 units/kg/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 mg/kg on Days 1, 3, and 5 had no antitumor effects as measured by survival of the animals. However, CPDG₁ (800 units/kg/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. These results demonstrate that CPDG₁ enhances the antitumor effects of TZT or DDMP.

¹ Supported by Grants CA-17245 and CA-08010 and Contract 1-CM-67068 from National Cancer Institute, Department of Health, Education, and Welfare.

² To whom requests for reprints should be addressed.

³ American Cancer Society Professor of Medicine and Pharmacology.

Received 3/10/78. Accepted 6/ 8/79.