Cytidine triphosphate synthetase (CTP synthetase) as a druggable target in cancer

Abstract

Cytidine triphosphate (CTP) synthetase is a key enzyme in the biosynthesis of pyrimidine ribonucleotides. The enzyme catalyzes the conversion of uridine triphosphate (UTP) to CTP and is the predominant pathway for the synthesis of CTP in proliferating and malignant tissues. Elevated CTP synthetase activity is seen in various malignancies, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), hepatoma, colon cancer and renal carcinoma, as well as non-Hodgkin's lymphoma (NHL). The high activity of the enzyme has led to the development of inhibitors as potential new therapeutic tools. The best explored inhibitor of CTP synthetase is cyclopentenyl cytosine (CPEC), which has been investigated in both preclinical and clinical studies. CPEC proved to profoundly inhibit CTP synthetase in vitro in colon carcinoma, ALL and AML cell lines. Moreover, CPEC has been shown to inhibit the growth of human and murine leukemia xenografts in vivo. A phase I clinical trial with CPEC as monotherapy showed that this compound inhibits CTP synthetase in surrogate tissues such as bone marrow. However, at the highest doses, CPEC proved to have severe cardiovascular toxicity, the mechanism of which has not been unraveled until recently. Additional preclinical studies did not show any cardiotoxicity in rats. There is probably a good rationale for using CPEC at lower doses, since it has been shown in preclinical models to display synergistic cytotoxic effects with other nucleoside analogues such as cytarabine or gemcitabine. In conclusion, CTP synthetase is a druggable target, especially for combination treatment of AML and ALL