The experimental cytotoxic
drug cyclopentenyl cytosine (CPEC) is an analogue of
cytidine. Besides its
antiviral effect, its potential use in the treatment of
cancer has become an important area of research. CPEC is activated by intracellular phosphorylation ultimately forming its metabolite
CPEC-TP.
CPEC-TP is a non competitive inhibitor of cytidine-5'-triphosphate
synthetase (
CTP-synthetase), an important
enzyme in the formation of
CTP. Studies have shown that
cancer cells have a high
CTP synthetase activity, thus making them interesting targets for
chemotherapy. CPEC has been preclinically studied in different
malignancy models. In vitro results on
leukemia show activity in the nanomolar range on several cell lines. However in vivo results are conflicting and the findings vary from increase in life span over 100% to only limited effectiveness. Interesting results have been obtained in colorectal and
neuroblastoma cells. In several
neuroblastoma cell lines incubation with CPEC in combination with
cytarabine or
gemcitabine has resulted in increased cell death compared to incubation with with only one of the agents. CPEC has been studied in a phase I trial in patients with solid
tumors. In five of 26 patients unexplained
cardiotoxicity (extreme
hypotension) occurred. The cardiotoxic effects could not be reproduced in animal models. However, precautions should be taken when using this
drug in future clinical trials. Low dosage of CPEC seems necessary and intensive cardiac monitoring is advisable. In this manuscript, it is demonstrated that CPEC has an anti-
cancer effect in several
tumor models: CPEC might be a potentially useful
drug in anticancer treatment.