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Antimetastatic Action and Hematological Toxicity of p-(3,3-Dimethyl-1-triazeno)benzoic Acid Potassium Salt and 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide Used as Prophylactic Adjuvants to Surgical Tumor Removal in Mice Bearing B16 Melanoma¹

Istituto di Farmacologia e Farmacognosia [G. S., T. G.], and Istituto di Chimica Farmaceutica [L. L., C. N.], Università di Trieste, I-34100 Trieste, Italy

The treatment of mice bearing i.m. B16 melanoma with equitoxic dosages of the clinically used 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) and of its benzenoid watersoluble analogue p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) prior to surgical tumor removal results in a remarkable proportion of cures, even when the treatment is started on already palpable tumors for which surgery alone is ineffective. The survival time of mice which are not cured is also significantly increased with DM-COOK. At the same time, DM-COOK does not affect artificial metastases or spontaneous metastases in mice undergoing surgery and treated with DM-COOK postoperatively. Inhibition of i.m. tumor growth in surgical experiments, and of s.c. tumors in mice not treated with surgery, is significant, although not as pronounced as is necessary to obtain significant prolongation of the life span of the host; the survival time of mice with s.c. tumors treated with both drugs is indeed not significantly increased. DM-COOK thus appears to exert selective antimetastatic effects, unrelated to cytotoxicity for tumor cells, against B16 melanoma in addition to those reported for Lewis lung carcinoma and M5 ovarian reticular cell sarcoma; its therapeutic usefulness is evidenced in adjuvant surgical experiments. DM-COOK, unlike DTIC, is devoid of hematological toxicity for the host. Since, in leukemic mice, it is at least as active as DTIC in increasing the life span of the treated animals, it appears to be an advantageous substitute for DTIC that could undergo preliminary clinical trial.

¹ Supported by the Italian National Research Council, Special Project "Control of Neoplastic Growth," Contract n.81.01380.96.

² To whom requests for reprints should be addressed, at Istituto di Farmacologia e Farmacognosia, via A. Valerio 32, 34100 Trieste, Italy.

Received 12/16/82. Accepted 9/26/83.