Antitumor efficacy of APO866 against Myla-2059, a model of cutaneous t-cell lymphoma

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 5610 APO866 (formerly FK866), an inhibitor of the enzyme nicotinamide phosphoribosyltransferase (NMPRTase), has been shown to inhibit the growth of an array of cancer cell lines in vitro and human tumor xenografts in vivo. The mechanism of action involves depletion of intracellular NAD+, resulting in apoptosis. During an in vitro screen of cancer cell lines to identify potential clinical targets, Myla-2059 cells, derived from a cutaneous T-cell lymphoma (CTCL), were found to be particularly sensitive to this agent (IC50=5.6 nM, n=3) as determined by FACS analysis with annexin/PI staining. In order to compare the efficacy of this agent with other agents shown to be active against CTCL in vivo, recipient female Balb/c nude mice were implanted subcutaneously with a Myla-2059 tumor fragment (approximately 50 mm3). When tumors reached treatment size (200 mm3), mice were treated with APO866 (20 mg/kg i.p., twice daily on days 1, 2, 3, 4, 8, 9, 10 and 11), methotrexate (0.3 mg/kg, i.v. on days 1 and 8), gemcitabine (120 mg/kg, i.v. on days 1, 4, 7 and 10) or with vehicle alone. Futhermore, the effect of combining APO866 with gemcitabine was investigated in vitro and in vivo. Both APO866 and the combination of APO866 with gemcitabine significantly reduced tumour growth compared to the control (p<0.01, one way anova) and in 3/9 animals in the APO866 and combination treatment groups, no regrowth of tumors was observed 45 days after start of treatment. Treatment with methotrexate and gemcitabine alone did not affect tumor growth. In summary we have shown that (i) Myla-2059 cells are sensitive to APO866 both in vitro and in vivo and (ii) this agent is more effective than other agents know to be active against CTCL. In conclusion these data support the clinical evaluation of APO866 in the treatment of CTCL.