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Experimental Antitumor Activity and Toxicity of a New Chemotherapeutic Agent, BBM 928A¹

Antitumor Biology Department, Pharmaceutical Research and Development Division, Bristol-Myers Co., Syracuse, New York 13201

The experimental antitumor activity and toxicity of a new antibiotic, BBM 928A (Luzopeptin A), was evaluated in mice. When administered as a suspension in 0.9% NaCl solution, the compound demonstrated good activity [median survival time of dying mice in a drug-treated group divided by the median survival time of 0.9% NaCl solution-treated mice in a tumor control group, (T/C) >150%] against i.p. B16 melanoma (B16) and i.p. P388 leukemia (P388) and weak activity (T/C of 125 to 150%) versus i.v. P388, i.p. L1210 leukemia (L1210), Lewis lung (LL), and Madison 109 lung (M109) carcinomas. In terms of tumor cell kill, BBM 928A induced net reductions in the body burdens of L1210 and P388 leukemias following single-drug injections but usually failed to yield net reductions following multiple-injection therapies despite achieving T/C >125%. Similarly, mice receiving i.p. implants of LL or M109 or i.v. implants of P388 did not generally achieve a net reduction in tumor burden following treatment with BBM 928A despite associated median increases in life span in excess of 25%, but multiple-injection therapies with BBM 928A against i.p. B16 did result in consistent net reductions in tumor levels. The 0.9% NaCl solution-suspended drug was inactive against i.p. Colon 26, s.c. M109, and s.c. B16. Compared to echinomycin, which it resembles in structure, BBM 928A performed very similarly against various murine tumors. For example, against i.p. B16, BBM 928A displayed superiority (average net cell kill advantage of 3.7 log₁₀), but it was comparable against i.p. L1210, P388, LL, and Colon 26 carcinomas, and slightly inferior in the i.p. M109 model. A soluble formulation of BBM 928A was found to be equivalent in activity to the suspension against i.p. P388 and B16 and was slightly active (T/C of 151% or 1.4 log₁₀ net cell kill) versus s.c. B16, whereas the suspension was inactive. In toxicity studies, the soluble formulation, a 0.1-mg/kg dose of which could kill 50% of the treated animals, did not cause leukopenia, nephrotoxicity, or hepatotoxicity as indicated by the lack of an effect upon WBC, blood urea nitrogen levels, and serum glutamic-pyruvic transaminase levels, respectively. Although there was no leukopenia, there were both a dose-related neutrophilia and lymphopenia. Because of its antitumor activity, novel structure, high potency (effective at µg/kg dose levels), strong binding affinity to DNA, and apparent lack of certain organ toxicities, further development of this compound or its analogs is being considered.

¹ Supported in part by NIH Contract N01-CM-07299.

² To whom requests for reprints should be addressed.

Received 3/11/82. Accepted 12/10/82.