Anti-tumour activity and toxicity of the new prodrug 9-aminocamptothecin glucuronide (9ACG) in mice.

Abstract

Cancer chemotherapy is limited by the modest therapeutic index of most antineoplastic drugs. Some glucuronide prodrugs may display selective anti-tumour activity against tumours that accumulate beta-glucuronidase. We examined the toxicity and anti-tumour activity of 9-aminocamptothecin glucuronide, a new glucuronide prodrug of 9-aminocamptothecin, to evaluate its potential clinical utility. 9-aminocamptothecin glucuronide was 25-60 times less toxic than 9-aminocamptothecin to five human cancer cell lines. Beta-glucuronidase activated 9-aminocamptothecin glucuronide to produce similar cell killing as 9-aminocamptothecin or topotecan. The in vivo toxicity of 9-aminocamptothecin glucuronide in BALB/c mice was dose-, route-, sex- and age-dependent. 9-aminocamptothecin glucuronide was significantly less toxic to female than to male mice but the difference decreased with age. 9-aminocamptothecin glucuronide and 9-aminocamptothecin produced similar inhibition (approximately 80%) of LS174T human colorectal carcinoma tumours. 9-aminocamptothecin glucuronide cured a high percentage of CL1-5 human lung cancer xenografts with efficacy that was similar to or greater than 9-aminocamptothecin, irinotecan and topotecan. The potent anti-tumour activity of 9-aminocamptothecin glucuronide suggests that this prodrug should be further evaluated for cancer treatment.

• Authors: Z M Prijovich, B-M Chen, Y-L Leu, J-W Chern, S R Roffler
• Journal: British journal of cancer (Br J Cancer) Vol. 86 Issue 10 Pg. 1634-8 (May 20 2002) ISSN: 0007-0920 [Print] England
• PMID: 12085215 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: comCopyright 2002 Cancer Research UK

Chemical References

• 9-aminocamptothecin glucuronide
• Antineoplastic Agents
• Glucuronides
• Prodrugs
• Topotecan
• Camptothecin

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use, toxicity)
• Breast Neoplasms (drug therapy, pathology)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use, toxicity)
• Drug Stability
• Female
• Glucuronides (pharmacokinetics, pharmacology, therapeutic use, toxicity)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (drug therapy, pathology)
• Prodrugs (pharmacology, therapeutic use, toxicity)
• Sex Factors
• Solubility
• Topotecan (pharmacology, toxicity)
• Tumor Cells, Cultured (drug effects)
• Weight Loss
• Xenograft Model Antitumor Assays