IN-SITU CYCLOPENTENYL CYTOSINE INFUSION FOR THE TREATMENT OF EXPERIMENTAL BRAIN-TUMORS

Citation
Jj. Viola et al., IN-SITU CYCLOPENTENYL CYTOSINE INFUSION FOR THE TREATMENT OF EXPERIMENTAL BRAIN-TUMORS, Cancer research, 55(6), 1995, pp. 1306-1309
Citations number
15
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
55
Issue
6
Year of publication
1995
Pages
1306 - 1309
Database
ISI
SICI code
0008-5472(1995)55:6<1306:ICCIFT>2.0.ZU;2-5
Abstract
Cyclopentenylcytosine (CPEC; NSC 375575) is a pyrimidine nucleoside an alogue that has potent antitumor effects when tested in vitro and also when tested in experimental tumors outside the central nervous system . CPEC exerts its antiproliferative effect through inhibition of CTP s ynthetase and consequent depletion of CTP and dCTP pools required for cell replication. Due to its poor penetration of the blood-brain barri er, CPEC has failed to demonstrate therapeutic efficacy in experimenta l brain tumors after systemic administration. We therefore examined th e in vivo activation, distribution, and antitumor effect of CPEC after long-term regional infusion of the drug directly into experimental br ain tumors in rats. HPLC analysis of CPEC incubated with homogenized h uman brain and brain tumor tissue showed minimal degradation of the dr ug over 24 h. Analysis of rat cerebral 9L gliosarcoma infused with tri tium-labeled CPEC demonstrated intratunoral accumulation of the active metabolite CPEC-triphosphate and concomitant depletion of CTP to a mu ch greater extent in tumor tissue than in the adjacent brain. Tumor ti ssue UTP also decreased, but no significant effects on other ribonucle oside hiphosphates were detected. Only trace amounts (<1%) of CPEC and its metabolites reached peripheral sites, including the liver and kid neys, after intratumoral infusion. Rats treated with continuous intrat umoral infusion of CPEC for 4 weeks using s.c. implanted osmotic pumps survived significantly longer than control rats receiving intratumora l saline or i.p. CPEC (P < 0.0001). Long-term intratumoral infusion of CPEC was not associated with any detectable toxicity. Our results sup port the feasibility of using intratumoral administration of CPEC as a regional therapy for malignant brain tumors.