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.