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Synergistic Antileukemic Effect of 6-Aminonicotinamide and 1,3-Bis(2-chloroethyl)-1-nitrosourea on L1210 Cells in Vitro and in Vivo¹

Division of Hematology/Oncology, Department of Medicine [N. A. B., D. M. C.], Division of Hematology/Oncology, Mallinckrodt Department of Pediatrics [T. J. V], Washington University School of Medicine, and The Jewish Hospital of St. Louis, St. Louis, Missouri 63110

A series of nicotinamide analogs were evaluated for their ability to inhibit L1210 cell poly(adenosine diphosphoribose) polymerase, and also for their ability to potentiate the cytocidal effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), nitrogen mustard, and -irradiation in L1210 cells growing in culture and in vivo. In vitro, nicotinamide, 5-methylnicotinamide, 6-aminonicotinamide, and benzamide effectively inhibited L1210 cell poly(adenosine diphosphoribose) polymerase; 1-methylnicotinamide, nicotinic acid, and benzoic acid did not. In culture, 6-aminonicotinamide potentiated the cytocidal effect of BCNU; however, it did not significantly potentiate the effects of nitrogen mustard or -irradiation. In vivo, both 6-aminonicotinamide and nicotinamide potentiated the cytocidal effect of BCNU; however, the concentrations of nicotinamide required for this effect were 10- to 20-fold higher than those of 6-aminonicotinamide. None of the analogs significantly potentiated the in vivo effect of nitrogen mustard or -irradiation. Treatment of L1210-bearing mice with varying combinations of BCNU and 6-aminonicotinamide produced a synergistic increase in life span; in some cases, the combination led to the production of long-term disease-free survivors.

¹ These studies were supported by NIH Grant CA24986 and American Cancer Society Grant CH134. Some cell culture media used in these experiments was prepared in a Cancer Center Facility supported by NIH Grant 2 P30 CA16217.

² Leukemia Society of America Scholar; to whom requests for reprints should be addressed, at Division of Hematology/Oncology, The Jewish Hospital of St. Louis, 216 South Kingshighway, St. Louis, Mo. 63110.

Received 4/28/82. Accepted 7/20/82.

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