Antiangiogenic potency of FK866/K22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma.

ABSTRACT

FK866/K22.175 (FK-866), developed as an anticancer agent, interferes with the NAD+ biosynthesis and therefore might have characteristics distinct from conventional chemotherapeutic agents. We investigated FK-866 in a murine renal cell carcinoma model (RENCA) to assess its antitumor, antimetastatic and antiangiogenic potency. FK-866 was administered twice daily on days 10 to 15 after intrarenal inoculation of RENCA cells in syngenic Balb/c mice at oral doses of 6, 10, 14 and 18 mg/kg to define the optimal dose related to toxicity. For efficacy studies, FK-866 was administered orally twice daily at doses of 6 and 10 mg/kg or twice daily at doses of 3 and 5 mg/kg on days 14 to 19 after tumor cell inoculation. Animals in the positive control group received 30 mg/kg TNP 470 subcutaneously on every other day beginning on day 1. On day 17, all animals were examined for blood flow in the left renal artery by color Doppler imaging (CDI). The animals were sacrificed on day 21 and analyzed for primary tumor weight and volume, number of metastases to the lung and abdominal lymph nodes and vessel density in tumor tissues. Doses of up to 6 mg/kg FK-866 were less toxic than treatment with TNP-470. Significant antitumor efficacy was observed for doses of > or = 10 mg/kg FK-866 only. In contrast, a significant decrease of vessel density in tumor tissues by up to 70% could be detected for all dose groups. Changes in blood flow in the tumor feeding renal artery could not be detected because of the profound strong tumor reduction. FK-866 has antitumoral and antimetastatic activity in RENCA mice. Furthermore, this is the first report to describe a strong antiangiogenic potency of FK-866.