The goal of this research proposal is to determine the biochemical pharmacology as well as certain aspects of the preclinical pharmacology and toxicology of the bleomycin analog Liblomycin. This drug, obtained from Profs, H. Umezawa and K. Umezawa at The Institute of Microbial Chemistry in Japan, is the first bleomycin analog to demonstrate significant antitumor efficacy without an apparent associated potential for pulmonary toxicity. Recent studies from our laboratory have also shown that it is the first bleomycin analog to demonstrate activity against human head and neck squamous carcinoma cells resistant to Blenoxane. Proposed studies may therefore serve as an initial point of departure for an investigation into the problem of resistance to bleomycin.
The specific aims of this grant include an investigation of the molecular pharmacology of Liblomycin with respect to its ability to 1) serve as a substrate for bleomycin hydrolase, 2) produce specific DNA injuries, and 3) bind to DNA in a specific manner (i.e. """"""""footprinting"""""""" studies). To investigate the spectrum of activity of Liblomycin (vs. bleomycin A2), the antitumor activity of this drug will be assessed against a number of specific human and murine tumor models. Equally important will be an assessment of this drug's relative ability to injure the lung. This will be accomplished through plethysmography studies, determination of pulmonary collagen synthetic rates and histopathology studies. An analytical assay for Liblomycin will be developed for use in the determination of drug pharmacokinetics and tissue distribution patterns. All of the above data will be essential in developing a preclinical understanding of Liblomycin prior to its possible clinical development both here in the U.S. and in Japan.
| Dogramatzis, D; Nishikawa, K; Newman, R A (1991) Interaction of hyperthermia with bleomycin and liblomycin: effects on CHO cells in vitro. Anticancer Res 11:1359-64 |
| Newman, R A; Siddik, Z H; Travis, E L et al. (1990) Assessment of pulmonary and hematologic toxicities of liblomycin, a novel bleomycin analog. Invest New Drugs 8:33-41 |
| Wassermann, K; Zwelling, L A; Lown, J W et al. (1990) Liblomycin-mediated DNA cleavage in human head and neck squamous carcinoma cells and purified DNA. Cancer Res 50:1732-7 |
| Tueni, E A; Newman, R A; Baker, F L et al. (1989) In vitro activity of bleomycin, tallysomycin S10b, and liblomycin against fresh human tumor cells. Cancer Res 49:1099-102 |
