Enhancement of antitumor activity of 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine and Baker's antifol (triazinate) with carboxypeptidase G1.

Abstract

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 grown 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.

• Authors: K K Kalghatgi, B A Moroson, C Horváth, J R Bertino
• Journal: Cancer research (Cancer Res) Vol. 39 Issue 9 Pg. 3441-5 (Sep 1979) ISSN: 0008-5472 [Print] United States
• PMID: 476673 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Folic Acid Antagonists
• Triazines
• metoprine
• triazinate
• Carboxypeptidases
• Pyrimethamine

Topics

• Animals
• Carboxypeptidases (administration & dosage, pharmacology)
• Carcinoma 256, Walker (drug therapy)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Synergism
• Drug Therapy, Combination
• Folic Acid Antagonists (administration & dosage)
• Male
• Pyrimethamine (administration & dosage, analogs & derivatives)
• Rats
• Time Factors
• Triazines (administration & dosage)