Selectivity of the Antimetastatic and Cytotoxic Effects of 1-p-(3,3-Dimethyl-1-triazeno)benzoic Acid Potassium Salt, (±)-1,2-Di(3,5-dioxopiperazin-1-yl)propane, and Cyclophosphamide in Mice Bearing Lewis Lung Carcinoma¹

The effects of two selective antimetastatic agents, 1-p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK), and (±)-1,2-di(3,5-dioxopiperazin-1-yl)propane, have been examined in comparison with those of a cytotoxic agent, cyclophosphamide, in mice bearing Lewis lung carcinoma. Cyclophosphamide at the two highest dosages causes a strictly related and pronounced inhibition (to less than 10%) of the weight of the s.c. tumor, spontaneous metastases, and lung colonies formed after i.v. injection of tumor cells (artificial metastases); this behavior is consistent with a purely cytotoxic mechanism. At the three dosages used, (±)-1,2-di(3,5-dioxopiperazin-1-yl)propane reduces the weight of spontaneous metastases to less than 3%. A dose-dependent reduction of artificial metastasis weight is also observed. At the highest dose, artificial metastasis weight is reduced to about 5%, and s.c. tumor mass is significantly lowered to 40%. These effects are consistent with the combined occurrence of cytotoxic and selective antimetastatic action, although the latter appears to be predominant. At the three dosages used, DM-COOK markedly depresses the weight and number of spontaneous metastases to about 10%, leaving the formation of artificial metastases unaffected and causing no significant effect on primary tumor growth. The effects of these agents on the fractional incorporation of [³H]thymidine in tumor cells further indicate that only DM-COOK is devoid of cytotoxic effects for pulmonary and s.c. tumors. In hosts pretreated with DM-COOK, no reduction in the formation either of spontaneous or of artificial metastases is observed.

These data indicate that DM-COOK acts directly on tumor cells and that it presumably inhibits their release from the primary tumor into the bloodstream.