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.