Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo. Laboratory investigation.

Abstract

OBJECT:

Irinotecan (CPT-11), a topoisomerase I inhibitor, is a cytotoxic agent with activity against malignant gliomas and other tumors. After systemic delivery, CPT-11 is converted to its active metabolite, SN-38, which displays significantly higher cytotoxic potency. However, the achievement of therapeutically effective plasma levels of CPT-11 and SN-38 is seriously complicated by variables that affect drug metabolism in the liver. Thus the capacity of CPT-11 to be converted to the active SN38 intratumorally in gliomas was addressed.

METHODS:

For in vitro studies, 2 glioma cell lines, U87 and U251, were tested to determine the cytotoxic effects of CPT-11 and SN-38 in a dose-dependent manner. In vivo studies were performed by implanting U87 intracranially into athymic/nude mice. For a period of 2 weeks, SN-38, CPT-11, or vehicle was administered intratumorally by means of an osmotic minipump. One series of experiments measured the presence of SN-38 or CPT-11 in the tumor and surrounding brain tissues after 2 weeks' exposure to the drug. In a second series of experiments, after 2 weeks' exposure to the drug, the animals were maintained, in the absence of drug, until death. The survival curves were then calculated.

RESULTS:

The results show that the animals that had CPT-11 delivered intratumorally by the minipump expressed SN-38 in vivo. Furthermore, both CPT-11 and SN-38 accumulated at higher levels in tumor tissues compared with uninvolved brain. Intratumoral delivery of CPT-11 or SN-38 extended the average survival time of tumor-bearing animals from 22 days to 46 and 65 days, respectively.

CONCLUSIONS:

These results demonstrate that intratumorally administered CPT-11 can be effectively converted to SN-38 and this method of drug delivery is effective in extending the survival time of animals bearing malignant gliomas.

• Authors: Weijun Wang, Alex Ghandi, Leonard Liebes, Stan G Louie, Florence M Hofman, Axel H Schönthal, Thomas C Chen
• Journal: Journal of neurosurgery (J Neurosurg) Vol. 114 Issue 3 Pg. 689-94 (Mar 2011) ISSN: 1933-0693 [Electronic] United States
• PMID: 20415520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Drug Implants
• Irinotecan
• Camptothecin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacokinetics)
• Brain (metabolism)
• Brain Neoplasms (drug therapy, metabolism)
• Camptothecin (analogs & derivatives, metabolism, pharmacokinetics)
• Cell Line, Tumor
• Cell Survival
• Chromatography, High Pressure Liquid
• Dose-Response Relationship, Drug
• Drug Delivery Systems
• Drug Implants
• Glioma (drug therapy, metabolism)
• Humans
• Irinotecan
• Mice
• Mice, Nude
• Survival Analysis
• Tissue Distribution