ANTITUMOR-ACTIVITY AND TOXICITY OF CONTINUOUS-INFUSION VERSUS BOLUS ADMINISTRATION OF BLEOMYCIN IN 2 HETEROTRANSPLANTED HUMAN TESTICULAR CANCER CELL-LINES

Abstract

The continuous infusion of the glycopeptide antibiotic cytotoxic agent bleomycin in comparison to bolus application has been postulated to be associated with increased antitumour activity and decreased toxicity, particularly pulmonary fibrosis. In the treatment of patients with testicular cancer, bleomycin is an essential agent and is currently used in continuous infusion and bolus application schedules in cisplatin-based combination therapy regimens. The current study addresses the antitumour activity and general toxicity of bleomycin given as continuous intraperitoneal infusion versus bolus application in human testicular cancer cell lines heterotransplanted into nude mice. Maximally tolerated doses for each administration route, defined as being the LD20 were applied (8.7 or 17.5 mg/kg days 1-7 continuous intraperitoneal infusion via osmotic mini pump or 40 mg/kg intraperitoneal bolus application on days 1, 5, 9). Bleomycin demonstrated antitumour efficacy at all concentrations used in comparison to untreated controls. There was no significant difference in antitumour activity between continuous or bolus application of bleomycin when the same cumulative doses were compared. Neither was there any difference with respect to bleomycin toxicity with 11 +/- 4 or 12 +/- 5% losses of body weight for continuous infusion regimens compared to 13 +/- 3% for bolus application. In a small subgroup of mice histological examination of the lungs demonstrated no signs of pulmonary fibrosis. In summary, using an established testicular cancer xenograft model in nude mice bolus application of bleomycin was as active as continuous infusion of this drug with no apparent difference in overall toxicity. Current standard treatment regimens using bolus application of bleomycin should not be altered without necessary reasons. Bleomycin pulmonary toxicity needs to be studied in clinical trials taking into account possible drug interactions in combination chemotherapy regimens and additional risk factors for pulmonary toxicity.