title: Cyclopentenyl cytosine has biological and anti-tumour activity, but does not enhance the efficacy of gemcitabine and radiation in two animal tumour models.
abstract: Cyclopentenyl cytosine (CPEC), targetting the de novo biosynthesis of cytidine triphosphate (CTP), increases the cytotoxicity of gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) alone and in combination with irradiation in several human tumour cells in vitro. We investigated whether CPEC enhances the therapeutic ratio of gemcitabine and irradiation in human pancreatic BxPC-3 xenografts and in rat syngeneic L44 lung tumours. These models were selected because gemcitabine and radiation are used to treat both pancreatic and lung cancer patients and both models differ in growth capacity and in gemcitabine-induced radiosensitisation. A profound dose-dependent CTP-depletion was observed after a single injection of CPEC in both tumour tissue and in normal jejunum. In both models, CPEC alone induced a slight but significant tumour growth delay. The combination of CPEC with gemcitabine, at time intervals that showed CTP-depletion after CPEC, enhanced neither tumour growth delay nor toxicity as compared to gemcitabine alone. In addition, no beneficial effect of CPEC was observed in combination with gemcitabine and radiation. These results suggest that CPEC and gemcitabine alone as well as in combination with radiation target a similar cell population in both tumour models. In conclusion, future clinical development of CPEC as a modulator of gemcitabine combined with radiation is unlikely.
authors.affiliation: Department of Radiation Oncology, Laboratory for Experimental Oncology and Radiobiology, Academic Medical Centre-University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Van Bree
authors.forename: Angeliqué D
authors.initials: AD
authors.lastname: Barten-Van Rijbroek
authors.forename: René
authors.initials: R
authors.lastname: Leen
authors.forename: Hans M
authors.initials: HM
authors.lastname: Rodermond
authors.forename: André B P
authors.initials: AB
authors.lastname: Van Kuilenburg
authors.forename: Henk B
authors.initials: HB
authors.lastname: Kal
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003570:Cytidine Triphosphate / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D051381:Rats; D011914:Rats, Inbred BN; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D003562:Cytidine; D003570:Cytidine Triphosphate; C045911:cyclopentenyl cytosine; D000093542:Gemcitabine