talisomycin and Neoplasms

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.

Topics: Adult; Aged; Bleomycin; Dose-Response Relationship, Drug; Drug Evaluation; Dyspnea; Female; Half-Life; Humans; Male; Middle Aged; Neoplasms

Tallysomycin S10b is a new bleomycin analogue. In animal studies it has shown the same degree of antineoplastic activity as bleomycin; however in contrast to that of bleomycin, its dose-limiting effect in animal systems is renal toxicity and its pulmonary toxicity is less pronounced. A total of 16 patients received tallysomycin S10b at three exploratory levels: 3 patients were given a dose of 1.25 mg/m2, 9 received 2.5 mg/m2 and 4 were given 5 mg/m2 as i.v. bolus injections twice weekly. Before treatment and every 3 weeks, plain chest X-rays, pulmonary function tests, renography and 51Cr-EDTA clearance were carried out. No renal toxicity was found in any of the treatment groups. In the first two groups no changes in chest X-rays were observed during treatment, whereas in the third group a decrease in single-breath carbon monoxide diffusion capacity (DLCO) was seen in one patient until the treatment was discontinued. Two of four patients receiving 5 mg/m2 developed interstitial pneumonitis at total doses of 104 and 160 mg, respectively. During the trial no haematologic or hepatic changes occurred due to the drug. The frequency of occurrence of skin changes, stomatitis and fever increased with the cumulative dose of tallysomycin S10b, and these side effects were similar to those seen with bleomycin. No tumor regression was seen during the trial. In contrast to the findings in previous animal studies, we found that the dose-limiting effect was pulmonary and not renal toxicity. The recommended dose for further phase II trials is 2.5 mg/m2 twice weekly, with careful monitoring of the pulmonary function.

Topics: Adult; Aged; Bleomycin; Chemical Phenomena; Chemistry; Drug Evaluation; Female; Humans; Kidney; Lung; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pigmentation Disorders; Pulmonary Fibrosis; Rectal Neoplasms; Respiratory Function Tests; Stomatitis