Bleomycin and cyclophosphamide toxicity in mice with damaged lung tissue.
The clinical use of several anticancer drugs, including bleomycin and cyclophosphamide (CP), is often associated with lung damage which progresses to fibrosis. The effect of existing lung damage on the toxicity of these agents has not been investigated. Male BALB/c mice were treated intraperitoneally with 400 mg/kg butylated hydroxytoluene (BHT), 100 mg/kg CP or 100 mg/kg bleomycin, alone or in combination. Based on analyses of pulmonary DNA synthesis, each agent alone elicited significant lung damage with cell proliferation, peaking on Day 4 for BHT, Day 7 for CP and Day 14 for bleomycin. Quantitatively, the BHT lesion was greater than CP which was much greater than bleomycin. Mice given 100, 75, 50, 40 or 25 mg/kg bleomycin 1 day after BHT exhibited 100, 90, 22, 20 and 21% mortality, respectively. Treatment with 100, 50, 40 or 25 mg/kg CP 1 day after BHT resulted in 100, 54, 33 and 0% mortality, respectively. No mice treated with BHT, bleomycin or CP alone died. Total lung hydroxyproline content, an index of fibrosis, was significantly increased 14 days after the initial treatment in mice given BHT and 50 mg/kg bleomycin compared to mice treated with BHT, bleomycin or vehicle alone. Mice treated with 50 mg/kg CP 1 day after BHT did not develop fibrosis in excess of that attributable to the BHT alone. Treatment of mice with 100 mg/kg CP followed 1 or 2 days later by 100 mg/kg bleomycin resulted in 20-40% mortality, but no increase in lung hydroxyproline content compared to CP alone. Bleomycin delayed the onset of lung cell proliferation normally seen after treatment with BHT while CP attenuated this cell division only after it had begun. Treatments involving BHT and bleomycin did not alter lung sulfhydryl content. These data indicate that overall toxicity is increased in mice pretreated with BHT and then given bleomycin or CP while lung injury is enhanced only after bleomycin. The mechanism of the interaction with bleomycin is not known but may be related to a rapid inhibition of lung repair and not to oxidative stress.
Kehrer
J P
JP
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712-1074.
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002084:Butylated Hydroxytoluene / Q000633:toxicity; D003520:Cyclophosphamide / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D008168:Lung / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013438:Sulfhydryl Compounds / Q000032:analysis
D013438:Sulfhydryl Compounds; D001761:Bleomycin; D002084:Butylated Hydroxytoluene; D003520:Cyclophosphamide; D004247:DNA