Abstract 2525: Intravenous infusions of TriN 2755, a new alkylating agent, inhibit the growth of human MDA-MB-231 breast tumor in nude rats

Abstract

Abstract Background: The new cytotoxic anti-neoplastic agent TriN 2755, containing a triazene unit with alkylating properties, exhibited a potent antitumor activity in a large panel of human xenograft tumor models in mice when dosed by IV bolus injection. In rat, dog and mini pig toxicity studies, TriN 2755 demonstrated a favourable safety profile. Here, we present efficacy data of TriN 2755 intravenously injected in the MDA-MB-231 tumor bearing Nude rat model. Material and methods: The breast tumors were induced subcutaneously by injecting 2×107 of MDA-MB-231 cells in 200 µl of RPMI 1640 containing matrigel (50:50, v:v). Tumor-bearing nude rats received a single 4-hour IV infusion of TriN 2755 at 30, 80 or 240 mg/kg/infusion or IV bolus injection of TriN 2755 at 160, 240 or 360 mg/kg/injection twice weekly for 4 consecutive weeks. Moreover, two groups of rats received a single 4-hour IV infusion of TriN 2755 at 240 mg/kg/infusion twice weekly for 4 consecutive weeks in combination with repeated weekly IV bolus injection of CPT-11 at 40 mg/kg/inj for 4 consecutive weeks or Docetaxel at 2.5 mg/kg/inj for 3 consecutive weeks. The treatment started when the mean tumor volumes reached about 400-800 mm3, and the antitumor activity of TriN 2755 was assessed as tumor volume inhibition relative to a vehicle control group (T/C value in %). Tolerability was analysed by recording mortality and body weight loss. Results: Repeated IV infusions of TriN 2755 were well tolerated by female nude rats bearing subcutaneous (SC) MDA-MB-231 tumors at all tested doses (no death, no body weight loss). The histopathological analysis of liver, kidneys, and bone marrow of treated rats revealed no treatment related changes. Based upon TriN 2755 antitumor efficacy criteria at 80 and 240 mg/kg when injected by IV infusion, and at 160, 240 or 360 mg/kg when injected by IV bolus displayed a marked, and dose-dependent antitumor activity against SC MDA-MB-231 tumor (Optimal T/C% values were 37, and 7%, 21, 19 and 12%, respectively) Tumor regressions were observed after two weeks of treatment for all rats treated with TriN 2755 administered by IV bolus or IV infusion of 240mg/kg/infusion. Tumor cells derived from TriN 2755 IV bolus treated rats had an impaired colony formation compared to non-treated tumors in vitro. Moreover, an enhancement of the antitumor activity of drugs alone was observed in the SC MDA MB-231 tumor bearing nude rats model when TriN 2755 at 240 mg/kg/infusion was combined with CPT-11 at 40 mg/kg/inj or Docetaxel at 2.5 mg/kg/inj. Conclusions: These results demonstrate that TriN 2755 dosed by IV infusion and IV bolus displayed a marked antitumor activity alone, and efficacy of IV infusion was increased by combination with CPT-11 or Docetaxel in SC nude rats human breast tumor model. TriN 2755 is currently under evaluation in phase I clinical trials for the treatment of solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2525. doi:10.1158/1538-7445.AM2011-2525