Tallysomycin S10b: Experimental antitumor activity and toxicity

Abstract

Tallysomycin S10b (TLM S10b), a structural analog of bleomycin (BLM), was evaluated and compared with BLM for antitumor activity in several murine tumor systems and for toxic effects in mice and rats. Neither TLM S10b nor BLM was effective against IP P388 and L1210 leukemias, whereas both drugs were active against IP P388/J leukemia (a BLM-sensitive subline). TLM S10b and BLM were both active against murine solid tumors, including SC B16 melanoma, IV Lewis lung carcinoma, SC Madison 109 lung carcinoma, SC CD8F1 mammary carcinoma and SC Colon 38 carcinoma. In human tumor xenograft models, TLM S10b was active against a colon tumor and had slight activity against breast and lung tumors. Compared with TLM S10b, BLM had less activity against the colon tumor, comparable activity against the breast tumor, and no effect against the lung tumor. A consensus of the antitumor data indicated that compared with BLM, TLM S10b had comparable or greater activity and was about twice as potent. TLM S10b and BLM had approximately equivalent LD50 values in mice. TLM S10b had minimal effects on WBC counts, blood urea nitrogen levels, and serum glutamic pyruvic transaminase levels in mice during the time periods monitored. These effects were comparable to or less pronounced than those of BLM. Both drugs caused dose-related increases in the whole-lung hydroxyproline content in mice, but the dose-response curves were not parallel. TLM S10b caused a larger increase than BLM at the lower doses and a smaller increase than BLM at the highest doses. In rats, TLM S10b and BLM caused comparable, significant decreases in lung mechanics; however, histopathological examination of the lungs indicated that TLM S10b caused less evidence of pulmonary toxicity than did BLM at comparable dose levels. TLM S10b was, therefore, generally comparable to BLM in causing pulmonary toxicity in mice and showed possibly less pulmonary toxicity in rats, while demonstrating approximately equivalent to four-fold greater potency, depending on the test system. It also appeared that TLM S10b caused less pulmonary toxicity than BLM in both mice and rats at doses approaching maximally tolerated levels. TLM S10b is currently undergoing phase I clinical evaluation.

Phase II study of tallysomycin S10b in patients with advanced head and neck cancer

“…In experimental tumor systems, tallysomycin S10b has a somewhat broader spectrum of activity than bleomycin [2]. Both compounds were active in vivo against a variety of murine tumors including the P388 leukemia, B16 melanoma, Lewis lung carcinoma, Sarcoma 180 and Madison 109 lung carcinoma.…”

An Evaluation of the Tumour Affinity of the Radioactive Cobalt Chelate of Tallysomycin S10b in Lymphoma-Bearing Mice

“…They also differ in the nature of the terminal amine side chain which, in the case of Tim Siob, is 1,4-diaminobutane (7). Tallysomycin S10b has been found to .0: be more effective than Blm and Tim A against several test tumour systems and to be generally less toxic (7,13).…”

Phase I trial of tallysomycin S10b, a bleomycin analogue

“…Subsequent studies comparing bleomycin and tallysomycin Sl0 b showed equal or greater activity of the latter against B16 melanoma, Lewis lung, CD8F 1 mammary and Colon 38 Carcinomas in mice [20]. In addition, tallysomycin $10 b exhibited 2-4-fold greater potency and equal or reduced pulmonary toxicity in mice and possibly in rats at doses near the maximally tolerated dose (MTD) [20].…”

“…Subsequent studies comparing bleomycin and tallysomycin Sl0 b showed equal or greater activity of the latter against B16 melanoma, Lewis lung, CD8F 1 mammary and Colon 38 Carcinomas in mice [20]. In addition, tallysomycin $10 b exhibited 2-4-fold greater potency and equal or reduced pulmonary toxicity in mice and possibly in rats at doses near the maximally tolerated dose (MTD) [20]. In BDF 1 mice implanted with B16 melanoma, Lewis lung and Colon 38 tumors, antineoplastic activity was documented for tallysomycin $10 b at dose ranges of 0.8-32 mg/kg/injection and 8-128 mg/ kg/injection for bleomycin, where the LDs0 for both drugs was equal or greater for tallysomycin S10 b [20].…”

“…In addition, tallysomycin $10 b exhibited 2-4-fold greater potency and equal or reduced pulmonary toxicity in mice and possibly in rats at doses near the maximally tolerated dose (MTD) [20]. In BDF 1 mice implanted with B16 melanoma, Lewis lung and Colon 38 tumors, antineoplastic activity was documented for tallysomycin $10 b at dose ranges of 0.8-32 mg/kg/injection and 8-128 mg/ kg/injection for bleomycin, where the LDs0 for both drugs was equal or greater for tallysomycin S10 b [20]. In these mice, pulmonary toxicity was assessed by whole lung hydroxyproline content.…”