Analysis of the prolonged infusion of DFP-10917, a deoxycytidine analog, as a therapeutic strategy for the treatment of human tumor xenografts in vivo

Abstract

2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofranocylcytosine (DFP-10917, CNDAC) is a 2'-deoxycytidine analog with antitumor activity against various tumor cells. However, a clinically available therapeutic regimen for this compound needs to be established and its functional mechanisms in relation to the dosing schedule need to be clarified. In this study, we evaluated the antitumor activity and toxicity of DFP-10917 by varying the dose and administration schedule in human solid tumor and leukemia xenografts in vivo. Compared to a 1-day infusion with a high-dose of DFP-10917 (30 mg/kg/day), a prolonged 14-day infusion with a low-dose (4.5 mg/kg/day) exerted superior tumor growth inhibitory effects without decreasing the body weights of mice in our human tumor xenograft model. In addition, we found that a 14-day infusion of low-dose DFP-10917 markedly prolonged the lifespan of nude mice bearing both acute leukemia and ovarian cancer cellderived tumors. On the other hand, gemcitabine (GEM) and cytosine arabinoside (Ara-C), which are similar deoxycytidine analogs and are widely used clinically as standard regimens, exerted less potent antitumor effects than DFP-10917 on these tumors. To elucidate the possible functional mechanisms of the prolonged infusion of DFP-10197 compared with that of GEM or Ara-C, the rate of DNA damage in CCRF-CEM and HeLa cells treated with DFP-10917, Ara-C and GEM was detected using a comet assay. DFP-10917, at a range of 0.05 to 1 μM, induced a clear tailed-DNA pattern in both the CCRF-CEM and HeLa cells; Ara-C and GEM did not have any effect. It was thus suggested that a low concentration and long-term exposure to DFP-10917 aggressively introduced the fragmentation of DNA molecules, namely the so-called double-strand breaks in tumor cells, leading to potent cytotoxicity. Moreover, treatment with DFP-10917 at a low-dose with a long-term exposure specifically increased the population of cells in the G2/M phase, while GEM reduced this cell population, suggesting a unique function (G2/M arrest) of DFP-10917. On the whole, our findings indicate that the prolonged infusion of low-dose DFP-10917 mainly displays a novel functional mechanism as a DNA-damaging drug and may thus prove to be useful in the treatment of cancer patients who are resistant to other cytosine nucleosides, or in patients in which these other nucleosides have been shown to be ineffective.