Acivicin. An antitumor antibiotic

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Acivicin (AT-125) is a Streptomyces sviceus fermentation product with demonstrated antitumor efficacy in preclinical mouse models.
• Its mechanism of action involves inhibiting enzymes crucial for amido transfer from L-glutamine, specifically CTP synthetase and XMP aminase.

Purpose of the Study:

• To evaluate the antitumor activity and toxicological profile of acivicin (AT-125) in preclinical models.
• To investigate the pharmacokinetic and pharmacodynamic differences influencing acivicin toxicity in various animal species and age groups.

Main Methods:

• Acivicin's efficacy was assessed in mouse tumor models (L1210, P388 leukemias, M5076 ovarian carcinoma, MX-1 breast tumor xenograft).
• Toxicology studies were conducted in dogs and monkeys, with pharmacokinetic analyses performed in mice to correlate drug clearance with observed toxicity.
• Systemic absorption and excretion patterns of acivicin were determined in mice via oral, intraperitoneal, and subcutaneous routes.

Main Results:

• Acivicin demonstrated significant antitumor activity across multiple mouse tumor models.
• Toxicological assessments revealed species-specific toxicities, with gastrointestinal effects predominating in dogs and monkeys.
• A notable finding was the increased resistance to acivicin toxicity in older male mice, linked to a twofold higher drug clearance rate compared to females and younger males.

Conclusions:

• Acivicin exhibits promising antitumor properties and acceptable preclinical toxicology, supporting its advancement.
• Understanding the pharmacokinetic basis for differential toxicity, particularly the sex and age-related differences in mice, is crucial for clinical application.
• The drug is progressing to Phase I clinical studies sponsored by the National Cancer Institute based on its preclinical data.