PARADOXICAL EFFECTS OF BLEOMYCIN AND HEAVY-WATER (D2O) IN MICE

Bleomycin (BLM) lacks many side effects of other cytostatic dregs. Pul monary toxicity is the major dose-limiting effect of BLM. This is base d in part on generation of free radicals. It is conceivable that deute rium in body fluids lessens the production of free radicals, thus prev enting or diminishing the morphologic expression of pulmonary BLM toxi city. We therefore studied the effect of moderate deuteration of body fluids on BLM-induced lung damage in BALB/c-mice. In addition to conve ntional histopathological methods, we used a vertical sectioning desig n for stereological estimation of pulmonary volumes and surface areas. BLM (low/medium/high dose: 25/50/75 IU/kg body weight) was injected i .p. once a week for 6 weeks. Half the mice drank deuterated water befo re, during and after BLM treatment. Three weeks after the last injecti on, the lungs were fixed by airway instillation. Deuterated animals tr eated with BLM lacked signs of irreversible BLM-induced pulmonary dama ge. Conversely, focal sub-pleural fibrosis and fibrosing alveolitis we re present in BLM-treated mice drinking tap water. Deuterated mice had stereological values for almost all lung parameters that were lower t han in non-deuterated mice. The organ-specific advantage of deuteratio n was offset by marked enhancement of systemic toxicity of BLM. We con clude that (1) moderate concentrations of deuterium may prevent the de velopment of fibrosing alveolitis in BLM-treated mice, possibly by red ucing proliferation of alveolar fibroblasts, and, less probably, by im pairing generation or enhancing capture of free radicals; (2) the toxi city of BLM was enhanced by ingestion of deuterium, resulting in morph ological liver alterations and increased mortality. (C) 1995 Wiley-Lis s, Inc.