Tallysomycin

Bleomycin is an agent with significant antitumor efficacy whose major dose limiting toxicity is pulmonary fibrosis. Attempts have thus been made to identify congeners with reduced toxicity and with comparable or greater antitumor activity. Tallysomycin S10b is a bleomycin analogue possessing significantly greater potency, equal or reduced lung toxicity, and slightly greater antineoplastic activity when compared to the parent compound in preclinical studies. This report describes our experience with tallysomycin S10b in 30 patients with a variety of non-hematologic neoplasms. Pulmonary toxicity, occurring in 4 patients, was the major toxicity. The recommended cumulative dose of tallysomycin S10b was difficult to establish from the results of this study, as pulmonary toxicity appeared to be more idiosyncratic than dose- or schedule-dependent. The employment of more sensitive methods for detecting pulmonary toxicity in this study suggest that tallysomycin S10b may have reduced pulmonary toxicity compared to the parent compound. Both bleomycin and tallysomycin S10b have similar t1/2 beta half-lives of 2-4 h. Six patients had prolonged terminal elimination half-lives of tallysomycin S10b, but no clear relationship between this phenomenon and efficacy or toxicity was evident. No complete or partial responses occurred. Disease stabilization occurred in 4 of 15 patients with diagnoses of renal cell carcinoma, rectal cancer and lung cancer. Five of eight patients with non-measurable disease had stable disease, including one with mesothelioma, one with carcinoma of the head and neck, two with renal cell cancer and one with colon carcinoma.

The biosynthetic gene clusters for the glycopeptide antitumor antibiotics bleomycin (BLM), tallysomycin (TLM), and zorbamycin (ZBM) have been recently cloned and characterized from Streptomyces verticillus ATCC15003, Streptoalloteichus hindustanus E465-94 ATCC31158, and Streptomyces flavoviridis ATCC21892, respectively. The striking similarities and differences among the biosynthetic gene clusters for the three structurally related glycopeptide antitumor antibiotics prompted us to compare and contrast their respective biosynthetic pathways and to investigate various enzymatic elements. The presence of different numbers of isolated nonribosomal peptide synthetase (NRPS) domains in all three clusters does not result in major structural differences of the respective compounds. The seemingly identical domain organization of the NRPS modules responsible for heterocycle formation, on the other hand, is contrasted by the biosynthesis of two different structural entities, bithiazole and thiazolinyl-thiazole, for BLM/TLM and ZBM, respectively. Variations in sugar biosynthesis apparently dictate the glycosylation patterns distinct for each of the BLM, TLM, and ZBM glycopeptide scaffolds. These observations demonstrate nature's ingenuity and flexibility in achieving structural differences and similarities via various mechanisms and will surely inspire combinatorial biosynthesis efforts to expand on natural product structural diversity.

The objective of this study was to compare the relative in vitro cytotoxicity of bleomycin to that of two newer-generation analogues, tallysomycin S10b and liblomycin. The latter compound is of particular interest as it has recently been shown in preclinical studies to be free of a potential to cause pulmonary injury and yet to possess only a minor potential to produce myelotoxicity. Using the adhesive tumor cell culture system, we evaluated the activity of these three drugs against a panel of 13 human tumors of various types. The range of concentrations chosen was determined and normalized using a nonleukemic permanent mouse hematopoietic progenitor cell line. Those drug concentrations achieving 90% inhibition of growth (IC90) against the murine cell line were: 6.11 microM bleomycin; 7.53 microM tallysomycin S10b; and 0.6 microM liblomycin. When tested against fresh human tumors at equally myelotoxic IC90 concentrations, bleomycin and tallysomycin S10b (nonmyelotoxic compounds) both achieved 90% growth inhibition of all tumors, while liblomycin (a myelotoxic compound) produced an IC90 inhibition in 69% of all tumors. A comparison of drug IC90 values against individual fresh tumors indicated a correlation between bleomycin and its structurally related analogue tallysomycin S10b. No such correlation, however, was seen with liblomycin in comparison to either bleomycin or tallysomycin S10b. The relative activity of liblomycin versus that of bleomycin and tallysomycin S10b varied with individual tumors tested. The response rate of liblomycin, a myelotoxic compound within this normalized range, appears promising. These data represent the first comparison of liblomycin to bleomycin against a spectrum of fresh human tumors using a stem cell assay technique.