Limited antitumor-effect associated with toxicity of the experimental cytotoxic drug cyclopentenyl cytosine in NOD/scid mice with acute lymphoblastic leukemia

The experimental cytotoxic drug cyclopentenyl cytosine (CPEC) is a non-competitive inhibitor of the enzyme cytidine triphosphate (CTP) synthethase. We evaluated the in vitro and in vivo antitumor activity of CPEC on human acute lymphoblastic leukemia (ALL) cell lines. CPEC displayed anti-leukemic activity with IC50 (after 3 days of incubation) ranging from 6 to 15 nM. Subsequently the in vivo activity of CPEC against primary human ALL was evaluated in a xenogeneic model of human ALL using NOD/scid mice inoculated with primary human ALL cells. In the model, only a marginal anti-leukemic activity was observed at 1.5 mg kg−1 (5 days per week) and 5 mg kg−1 (2 days per week), however, this activity was associated with severe systemic toxicity. The observed toxicity was not specific for the NOD/scid model, as toxicity at comparable treatment intensity was also observed in Balb/c mice. In conclusion, although CPEC showed antitumor activity against human ALL cells in vitro, its activity in the in vivo human leukemia model was only marginal and accompanied by severe toxicity.