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Studies on the Pharmacology and Cytokinetics of 2,3-Dihydro-1H-imadazo[1,2-b]pyrazole (NSC 51143) with P815 Mastocytoma Cells¹

University of Miami School of Medicine, Departments of Oncology [L. M. A.], Pharmacology, and Surgical Oncology [J. T. T.], Miami, Florida 33101

A study has been made of the biochemical, cytokinetic, and pharmacological effects of pyrazole-imidazole (NSC 51143) (IMPY) on P815 mastocytoma ascites cells maintained in mice and of cells maintained in culture.

The distribution phase of IMPY equivalents from the peritoneal fluid of the mouse was found to be two hr, with an elimination phase of 69 hr. No consistent alteration in the ribonucleotide pools of the ascites tumor cells in vivo was observed by high-pressure liquid chromatography using i.p. doses of IMPY up to 1000 mg/kg (25% increase in survival). Correspondingly, no significant alteration occurred in the proportion of cells in G₀, G₁, S, or G₂ + M in vivo by flow cytometric analysis. This is in contrast to the in vitro data which showed a significant blockage in S phase (50% effective dose, 1.6 x 10^-4 M). Using Dowex 1 chromatography of extracts from ascites tumor cells treated with IMPY in vivo, several intracellular drug metabolites were detected, and their proportion was noted to change with time. No such metabolism was detected in vitro. Some radiolabeled drug was detected in RNA and DNA from the cold, acid-insoluble fraction of ascites tumor cells. Analysis of alkaline sucrose sedimentation indicated that part of the radiolabeled IMPY was in the heavy-sedimenting DNA fraction.

¹ Support of this work has been in part from the Biological Handling Program (PROPHET Computer system) of the Division of Research Resources, NIH, Center Grant CA-14395, and in part from the Women's Cancer Association of Miami.

² Present address: College of Medicine, Department of Biophysics, East Tennessee State University, Johnson City, Tenn. 37601.

Received 12/12/79. Accepted 7/28/80.