Abstract 4525: Combined antitumor activity of the epirubicin-incorporating polymeric micelle NC-6300 and the DACHPt-incorporating polymeric micelle NC-4016 in mice bearing human gastric cancer xenografts

Background: Several anticancer agent (ACA)-incorporating polymeric micelles are known to accumulate effectively in tumors and exert sufficient antitumor effects via the enhanced permeability and retention (EPR) effect. These agents are now under clinical evaluation. However, there have been few reports of the antitumor effects of combinations of these agents. We evaluated the effects of a combination of the epirubicin-incorporating micelle NC-6300 and the DACHPt (oxaliplatin parent complex)-incorporating micelle NC-4016 on human gastric cancer 44As3Luc xenografts. Methods: First, we evaluated the cytotoxic effects of a combination of NC-6300+NC-4016 or epirubicin+oxaliplatin in vitro in 44As3Luc cells by using the combination index method. Next, to evaluate the antitumor effects, NC-6300 (8 mg/kg) and NC-4016 (4 mg/kg) or epirubicin (8 mg/kg) and oxaliplatin (4 mg/kg) were intravenously administered once a week for 3 weeks to mice bearing 44As3Luc xenografts implanted subcutaneously or orthotopically. Drug distribution was analyzed by high-performance liquid chromatography or inductively coupled plasma mass spectrometry. To evaluate the typical cumulative toxicity of each drug, we examined cardiotoxicity and neurotoxicity in the mice by using echocardiography and by measuring the latency of paw withdrawal in response to a noxious mechanical stimulus following long-term administration of each drug. Results: In our in vitro assay the combination of NC-6300+NC-4016 had more synergistic activity than that of epirubicin+oxaliplatin. Compared with the conventional anticancer drug combination, the combination of micelles had significantly greater antitumor activity against 44As3Luc cells in the subcutaneous tumor model and prolonged overall survival in the orthotopic tumor model. A high drug concentration of each ACA was detected in the tumor tissue in the case of co-administration of the two micelle formulations. Both cardiotoxicity and neurotoxicity were significantly lower in the micelle treatment group than in the conventional group. Conclusion: These data warrant the clinical evaluation of combination therapy with ACA-incorporating micelles. Citation Format: Yoshiyuki Yamamoto, Ichinosuke Hyodo, Misato Takigahira, Yoshikatsu Koga, Masahiro Yasunaga, Mitsunori Harada, Tatsuyuki Hayashi, Yasuki Kato, Yasuhiro Matsumura. Combined antitumor activity of the epirubicin-incorporating polymeric micelle NC-6300 and the DACHPt-incorporating polymeric micelle NC-4016 i