Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo. Laboratory investigation.
OBJECTIVE
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.
Wang
Weijun
W
Department of Neurosurgery, University of Southern California, Los Angeles, California, USA.
Ghandi
Alex
A
Liebes
Leonard
L
Louie
Stan G
SG
Hofman
Florence M
FM
Schönthal
Axel H
AH
Chen
Thomas C
TC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004343:Drug Implants; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D016019:Survival Analysis; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D004343:Drug Implants; D000077146:Irinotecan; D002166:Camptothecin