Effects of 5,8-dideazaisopteroylglutamate (IAHQ) on L1210 leukemia in mice when given alone and in combination with methotrexate,probenecid, or verapamil

Summary The folate analogue 5,8-dideazaisopteroylglutamate (IAHQ; NSC-289517) inhibits the growth of a variety of human tumor cells in vitro such as colon, breast and osteosarcoma. Since IAHQ has only modest activity against L1210 leukemia in mice, it was tested in combination with methotrexate (MTX), probenecid, or verapamil in an effort to enhance efficacy. Single drug or drug combinations were administered every other day 3 or 5 times beginning on day 1 following the administration of 10⁶ L1210 cells per animal. The combination of IAHQ (100 mg/kg) plus MTX (10 mg/kg) produced a decrease in mean survival time compared to that of MTX alone, regardless of whether the drugs were initiated on the same day or whether either one was started 2 days prior to the other. IAHQ (150 mg/kg) plus verapamil (5, 10, or 20 mg/kg) did not alter significantly the results produced by IAHQ alone. However, the combination of IAHQ (150 mg/kg) plus probenecid (250 mg/kg) augmented the increase in mean survival time above that produced by IAHQ alone by 82% (p=>0.001). The results suggest that probenecid could be used to enhance the effectiveness of IAHQ against solid tumors such as colon adenocarcinoma.Supported by Public Health Service Grant CA-25014 (National Cancer Institute) from the National Institutes of Health, Department of Health and Human Services, by the Veterans Administration, and by VA-NCI Interagency Agreement IGA V101 (134A) P-77014. Presented in part at the Annual Meeting of the Southeastern Section, Society for Experimental Biology and Medicine, Charleston, SC, November 14–15, 1985.