Abstract 2569: Combination of the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin produces complete remissions in an ovarian A2780 xenograft model

Abstract

Abstract INNO-206, the (6-maleimidocaproyl)hydrazone of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that has demonstrated superior antitumor efficacy in eight murine tumor models compared to doxorubicin. After intravenous administration, INNO-206 rapidly binds to the cysteine-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. It has shown objective responses in a phase I study, and phase II studies are planned for 2011 at the recommended dose of 260 mg/m2 i.e. an approximate 4-fold increase over the standard dose for doxorubicin. Interestingly, in contrast to free doxorubicin, which primarily locates in the nucleus, INNO-206, mainly accumulates in the cytoplasm. Furthermore, the binding of INNO-206 to albumin and the resulting EPR-mediated accumulation and distribution in the tumor will differ from the distribution of free doxorubicin which will be mediated by diffusion. There might thus be a rationale to combine the two drug formulations for obtaining an optimal antitumor effect. Indeed, in cell culture experiments using A2780 cells, a moderate synergy was found at a 5:1 ratio of free Doxo : INNO-206. In a next step, we therefore tested whether a combination of suboptimal doses of INNO-206 with doxorubicin improved the therapeutic efficacy of INNO-206 or doxorubicin at their respective maximum tolerated doses (MTDs) in the mouse model. We treated nude mice with subcutaneously growing ovarian A2780 xenografts on a weekly schedule with 2 × 8 mg/kg doxorubicin (MTD), 3 × 24 mg/kg INNO-206 (doxorubicin equivalents) (MTD) and a combination of 3 × 12 mg/kg INNO-206 (doxorubicin equivalents) and 3 × 4 mg/kg doxorubicin. In the combination protocol, INNO-206 was administered 6 h prior to doxorubicin treatment. Doxorubicin showed a very moderate effect and a body weight loss of -21 %, whereas INNO-206 and also the combination produced complete remissions. The combination, however, was much better tolerated causing a body weight loss of -12 % compared to -31 % for INNO-206. The surprising result of this experiment is that the doses used in the combination regimen were able to induce complete remission and the best tolerability considering that when dosed individually at these doses, neither doxorubicin or INNO-206 would have produced such an impressive antitumor response. This work is an impetus for investigating further combinations of albumin-binding prodrugs with clinically established anticancer agents. 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 2569. doi:10.1158/1538-7445.AM2011-2569