Paradoxical effects of bleomycin and heavy water (D2O) in mice.
Bleomycin (BLM) lacks many side effects of other cytostatic drugs. Pulmonary toxicity is the major dose-limiting effect of BLM. This is based in part on generation of free radicals. It is conceivable that deuterium in body fluids lessens the production of free radicals, thus preventing or diminishing the morphologic expression of pulmonary BLM toxicity. We therefore studied the effect of moderate deuteration of body fluids on BLM-induced lung damage in BALB/c-mice. In addition to conventional histopathological methods, we used a vertical sectioning design 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 before, during and after BLM treatment. Three weeks after the last injection, the lungs were fixed by airway instillation. Deuterated animals treated with BLM lacked signs of irreversible BLM-induced pulmonary damage. Conversely, focal sub-pleural fibrosis and fibrosing alveolitis were present in BLM-treated mice drinking tap water. Deuterated mice had stereological values for almost all lung parameters that were lower than in non-deuterated mice. The organ-specific advantage of deuteration was offset by marked enhancement of systemic toxicity of BLM. We conclude that (1) moderate concentrations of deuterium may prevent the development of fibrosing alveolitis in BLM-treated mice, possibly by reducing proliferation of alveolar fibroblasts, and, less probably, by impairing generation or enhancing capture of free radicals; (2) the toxicity of BLM was enhanced by ingestion of deuterium, resulting in morphological liver alterations and increased mortality.
Gaeng
D P
DP
Institute of Pathology, University of Bern, Switzerland.
Geiser
M
M
Cruz-Orive
L M
LM
Larsen
S E
SE
Schaffner
T
T
Laissue
J A
JA
Altermatt
H J
HJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D017666:Deuterium Oxide / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000166:cytology / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D016166:Free Radical Scavengers; D011837:Radiation-Protective Agents; D001761:Bleomycin; D017666:Deuterium Oxide