Abstract 5513: Synergistic antitumor activity of NK012, a micelle-forming macromolecular prodrug of SN-38, combined with platinum compounds in human cancer xenograft models

Abstract

Abstract Irinotecan (CPT-11) is clinically used to treat various tumors, but low enzymatic conversion to its active metabolite, SN-38, limits its therapeutic effect. NK012, a micelle-forming macromolecular prodrug of SN-38, accumulates in tumor tissue and gradually releases SN-38 in enzyme-independent manner. NK012 showed much stronger growth inhibitory effects than CPT-11 at maximum tolerated dose (MTD) against all tested xenografted human tumors. Furthermore, NK012 showed much stronger antitumor activities than other cytotoxic agents clinically used for cancer treatment (taxanes, doxorubicin, carboplatin etc.). Here, we report combination antitumor effects of NK012 with platinum compounds in human breast cancer, non-small cell lung cancer, colorectal cancer and hepatocellular cancer xenografts in nude mice. The dose of NK012 was set at 1.9-3.8 mg/kg/day to be sub-optimum for complete regression depending on the cell line. NK012 and carboplatin were administered by q7dx3. Although both of NK012 and carboplatin were ineffective as single agent (minimum T/C values >50%), their combination was effective (minimum T/C value = 8%) to cause tumor regression in MC-05-JCK breast cancer. In MC-05-JCK breast cancer, the TGDs (Tumor Growth Delay; tumor tripling time over control group delayed by treatment / tumor tripling time of control group × 100) by NK012 1.9 mg/kg/day, carboplatin 50 mg/kg/day (67% of MTD), and their combination were 41%, 29%, and 286%, respectively. In NCI-H460 non-small cell lung cancer, the TGDs by NK012 3.8 mg/kg/day, carboplatin 75 mg/kg/day (MTD), and their combination were 90%, 71%, and 403%, respectively. In Co-3 colorectal cancer, the TGDs by NK012 3.8 mg/kg/day, carboplatin 75 mg/kg/day, and their combination were 358%, 97%, and >489%, respectively. Thus, combination of NK012 with carboplatin showed remarkably synergistic effects, and it didn't accompany toxicity exacerbation. Similarly, combination of NK012 with cisplatin exhibited remarkable synergistic effects in Li-07-JCK hepatocellular cancer. The TGDs by NK012 3.8 mg/kg, one shot, cisplatin 10 mg/kg, one shot, and their combination were 58%, 136%, and 455%, respectively. These results indicate that NK012 and platinum compounds combination regimen would be effective for treatment of patients with solid tumors including breast, non-small cell lung, colorectal and hepatocellular carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5513.