A preclinical study on the rescue of normal tissue by nicotinic acid in high-dose treatment with APO866, a specific nicotinamide phosphoribosyltransferase inhibitor.

摘要

Inhibitor of nicotinamide phosphoribosyltransferase APO866 is a promising cancer drug currently in phase II clinical trials in oncology. Here, we present a strategy for increasing the therapeutic potential of APO866 through the rescue of normal tissues by coadministration of nicotinic acid (Vitamin B(3)). We examined the toxicity profile of APO866 in B6D2F1 mice and the effect of oral administration of nicotinic acid on tissue toxicity. Nicotinic acid (50 mg/kg) protects mice from death and severe toxicity from an APO866 dose (60 mg/kg) four times the monotherapy maximum tolerated dose (15 mg/kg). In a panel of six cancer cell lines, we find that three (including ML-2 cells) are protected by nicotinic acid in vitro, whereas the cytotoxicity of APO866 remains unaffected in the remaining three (including A2780 cells). A selective biomarker for the protection by nicotinic acid was subsequently identified by quantitative RT-PCR. The expression of nicotinic acid phosphoribosyltransferase is low in the cell lines not rescued from APO866 by nicotinic acid compared with protected cell lines. The findings in cell lines translated into xenograft models in which the combination of 50 mg/kg nicotinic acid and 50 mg/kg APO866 in mouse xenografts of A2780 cells increased life span by >3-fold compared with standard treatment of 15 mg/kg, and the effect of APO866 was clearly decreased when using the same treatment paradigm in ML-2 xenografts. In conclusion, the combination of high doses of APO866 with rescue by nicotinic acid may significantly increase the therapeutic potential in a subset of cancers with low expression of nicotinic acid phosphoribosyltransferase.