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Enhancement of Experimental Lung Metastases by Cultured B16 Melanoma Cells Treated with (±)-1,2-Bis(3,5-dioxoplperazin-1-yl)propane (ICRF-159)¹

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

The in vitro colony-forming efficiency of exponentially growing B16 melanoma cells was significantly decreased after an exposure to concentrations of (±)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ICRF-159) of 20 µM or more. Under identical conditions ICRF-159 significantly increased the in vivo lung colony-forming efficiency of these cells. Thus, 24 hr after 20 µM ICRF-159 the ability of melanoma cells to form colonies in vitro was reduced by 89%, while the lung colony-forming efficiency of these same cells was enhanced 5.5-fold after tail vein injection into syngeneic mice. The ratio of in vivo to in vitro colony-forming efficiency of cells treated with 20 µM ICRF-159 for 24 or 48 hr was elevated 50- to 110-fold above that seen with untreated cells. Mice inoculated s.c. with ICRF-159-treated cells developed tumors later and survived longer than did mice receiving untreated control cells. The increase in the tumor latent period and the mean survival time was consistent with a 90% decrease in cell viability observed with the in vitro colony-forming assay. The enhancement of the ability of B16 cells to form lung colonies after treatment with ICRF-159 appears to be due to a drug-induced change in the cells rather than to the presence in the cell population of a mixture of dead and viable cells. An increase in cell volume and in the incorporation of precursors of glycosaminoglycans was observed after treatment with ICRF-159 and may be responsible for the enhanced lung colony formation. The findings suggest that ICRF-159 may increase the ability of circulating melanoma cells to implant and grow in susceptible distant organs. Since circulating tumor cells are often found in patients with solid tumors, the metastatic potential of these cells may be enhanced by only partially effective chemotherapy.

¹ Supported in part by Grants CA-02817 and CA-16359 from the National Cancer Institute, Department of Health, Education and Welfare.

² Recipient of an American Cancer Society Postdoctoral Fellowship, PF-1303, and a National Cancer Institute, Department of Health, Education and Welfare, Postdoctoral Fellowship, CA-05924.

Received 2/ 3/78. Accepted 5/ 3/78.