Preliminary toxicity studies with the DNA-binding antibiotic, CC-1065

Area of Science:

• Pharmacology
• Toxicology
• Oncology

Background:

• The DNA-binding antibiotic CC-1065 previously demonstrated lifespan extension in tumor-bearing mice but was not curative.
• Therapeutic doses of CC-1065 were investigated for potential toxic effects beyond its antineoplastic activity.

Purpose of the Study:

• To investigate the delayed hepatotoxicity of CC-1065 at therapeutic antineoplastic doses.
• To determine the dose-response relationship and mechanisms of CC-1065-induced liver injury.
• To assess the efficacy of potential protective agents against CC-1065 hepatotoxicity.

Main Methods:

• Administration of CC-1065 to non-tumor-bearing mice via intravenous (IV) and intraperitoneal (IP) routes at varying doses.
• Determination of median lethal dose (LD50) values for single and multiple dosing regimens.
• Histopathological examination of liver tissues to identify mechanisms of toxicity.
• Co-administration of CC-1065 with potential protective agents (WR-2721, N-acetylcysteine, phenobarbital, Aroclor 1254, 3-methylcholanthrene).
• Similar toxicity studies were conducted in rabbits.

Main Results:

• Lethal delayed hepatotoxicity was observed in mice at therapeutic doses of CC-1065.
• Delayed deaths occurred up to 70 days post-administration, with distinct hepatic pathologies at high (acute necrosis) and low (mitochondrial changes) dose ranges.
• IV LD50 was 9 µg/kg (single dose) and 0.3 µg/kg/day (5 doses); IP LD50 ranged from 0.53-6.90 µg/kg (single dose) and 0.14 µg/kg/day (5 doses).
• None of the tested agents (WR-2721, N-acetylcysteine, etc.) prevented or altered the toxicity or LD50.
• Rabbits exhibited similar dose-dependent hepatotoxicity on a body surface area basis.

Conclusions:

• CC-1065 exhibits significant delayed hepatotoxicity at therapeutic doses, suggesting a potential limitation for its clinical use.
• Distinct mechanisms of liver injury appear to operate at different dose levels of CC-1065.
• The observed toxicity in mice was not mitigated by standard protective agents, and similar toxic effects were noted in rabbits.