Anti-tumour activity and toxicity of the new prodrug 9-aminocamptothecin glucuronide (9ACG) in mice.
Bottom Line: Cancer chemotherapy is limited by the modest therapeutic index of most antineoplastic drugs.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.
Affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 115, and ICTM, Center for Chemistry, Belgrade, Yugoslavia.Show MeSH
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Mentions: A single s.c. injection of 2.5 mg kg−1 9AC suspended in lipiodol caused minimal toxicity with 10% weight loss whereas a dose of 5 mg kg−1 produced about 20% weight loss (results not shown). Mice that were i.p. injected with 50 mg kg−1 9ACG experienced progressive weight loss and died within 6 days (results not shown). In contrast, all mice that were i.v. injected with 25 or 50 mg kg−1 9ACG experienced dose-dependent weight loss until day 6 followed by rapid and complete recovery within a week. A more detailed study of toxicity performed in 7–8 week old male and female mice with 50 mg kg−1 9ACG (Figure 1Figure 1
Affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 115, and ICTM, Center for Chemistry, Belgrade, Yugoslavia.