Assessment of pulmonary and hematologic toxicities of liblomycin, a novel bleomycin analog.
The antitumor efficacy as well as hematologic and pulmonary toxicity of Liblomycin, a new lipophilic analog of bleomycin, was evaluated in BDF1 mice. In comparison to bleomycin which was without any antitumor efficacy against P388 leukemia, a dose of 10 mg/kg Liblomycin administered on a daily schedule for 10 consecutive days resulted in a significant increase in animal survival (% T/C of 190). This therapeutic dose and schedule of drug administration did not produce any evidence of pulmonary histopathologic injury; at a similar dose and schedule bleomycin resulted in greater than 40% consolidation of alveolar lung space. Mouse lung collagen synthesis measured as rate of [3H]hydroxyproline formation was increased almost 4-fold by bleomycin 7 days following a single maximally tolerated i.v. injection (133 mg/kg); in contrast, Liblomycin (60 mg/kg) did not significantly alter the rate of lung collagen synthesis compared to saline injected control animals. Lung function was assessed by whole body plethysmography. Bleomycin produced an increase in breathing rates above control values by day 15 following administration of drug at 10 mg/kg (d1-10). Mice treated with Liblomycin did not exhibit an increased rate of breathing. Liblomycin, in contrast to bleomycin, produced mild and transient leukopenia and thrombocytopenia suggesting that this toxicity will be a limiting one in future clinical trials. The only other toxicity noted in this study was the appearance after repeated intraperitoneal administration of Liblomycin of a hepatic collagenous fibrous capsule. The capsule formation resulted in an abnormal and grossly lobulated liver which was believed to have affected animal survival. Intravenous administration of Liblomycin, however, was not associated with any detectable hepatic injury.
Newman
R A
RA
Department of Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Siddik
Z H
ZH
Travis
E L
EL
Followill
D
D
Ayele
W
W
Burditt
T
T
Krakoff
I H
IH
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology / Q000633:toxicity* / Q000031:analogs & derivatives; D003094:Collagen / Q000096:biosynthesis; D006402:Hematologic Diseases / Q000139:chemically induced; D007941:Leukemia P388 / Q000188:drug therapy; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010993:Plethysmography, Whole Body
D001761:Bleomycin; C054113:liblomycin; D003094:Collagen