title: In situ cyclopentenyl cytosine infusion for the treatment of experimental brain tumors.
abstract: Cyclopentenylcytosine (CPEC; NSC 375575) is a pyrimidine nucleoside analogue 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 synthetase and consequent depletion of CTP and dCTP pools required for cell replication. Due to its poor penetration of the bloodbrain barrier, CPEC has failed to demonstrate therapeutic efficacy in experimental brain tumors after systemic administration. We therefore examined the in vivo activation, distribution, and antitumor effect of CPEC after long-term regional infusion of the drug directly into experimental brain tumors in rats. HPLC analysis of CPEC incubated with homogenized human brain and brain tumor tissue showed minimal degradation of the drug over 24 h. Analysis of rat cerebral 9L gliosarcoma infused with tritium-labeled CPEC demonstrated intratumoral accumulation of the active metabolite CPEC-triphosphate and concomitant depletion of CTP to a much greater extent in tumor tissue than in the adjacent brain. Tumor tissue UTP also decreased, but no significant effects on other ribonucleoside triphosphates were detected. Only trace amounts (< 1%) of CPEC and its metabolites reached peripheral sites, including the liver and kidneys, after intratumoral infusion. Rats treated with continuous intratumoral infusion of CPEC for 4 weeks using s.c. implanted osmotic pumps survived significantly longer than control rats receiving intratumoral saline or i.p. CPEC (P < 0.0001). Long-term intratumoral infusion of CPEC was not associated with any detectable toxicity. Our results support the feasibility of using intratumoral administration of CPEC as a regional therapy for malignant brain tumors.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892-4255.
authors.forename: J J
authors.initials: JJ
authors.lastname: Viola
authors.forename: R
authors.initials: R
authors.lastname: Agbaria
authors.forename: S
authors.initials: S
authors.lastname: Walbridge
authors.forename: E M
authors.initials: EM
authors.lastname: Oshiro
authors.forename: D G
authors.initials: DG
authors.lastname: Johns
authors.forename: J A
authors.initials: JA
authors.lastname: Kelley
authors.forename: E H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: Z
authors.initials: Z
authors.lastname: Ram
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001711:Biotransformation; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003562:Cytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003570:Cytidine Triphosphate / Q000378:metabolism; D004355:Drug Stability; D018316:Gliosarcoma / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003562:Cytidine; D003570:Cytidine Triphosphate; C045911:cyclopentenyl cytosine