Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model

In this work, we evaluated combinations of doxorubicin with INNO-206, a (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) that is currently undergoing two phase II clinical trials, in a primarily chemoresistant tumor indication, i.e. pancreatic cancer. Thus, we compared the antitumor efficacy and tolerability of the following weekly intravenous treatments in the MIA PaCa-2 xenograft model: 3 x 6 mg doxorubicin (MTD), 3 x 24 mg/kg DOXO-EMCH (doxorubicin equivalents, MTD), 3 x 3 mg/kg doxorubicin followed 6 h later by 3 x 12 mg/kg DOXO-EMCH, and 3 x 12 mg/kg DOXO-EMCH followed 6 h later by 3 x 3 mg/kg doxorubicin. Whereas therapy with doxorubicin only produced a moderate tumor inhibition, all other therapy arms induced complete and partial remissions up to the end of the experiment on day 43. Although the total amount of doxorubicin equivalents is 72 mg/kg when DOXO-EMCH is administered alone, but only 45 mg/kg doxorubicin equivalents are administered in the combination regimens, the antitumor efficacy in all treated groups was essentially identical, a surprising finding of this study. However, there were significant differences in the tolerability as assessed by the body weight changes: whereas therapy at the MTD of DOXO-EMCH (3 x 24 mg/kg) produced a body weight loss of -16% including one death, therapy with 3 x 12 mg/kg DOXO-EMCH followed 6 h later by 3 x 3 mg/kg doxorubicin produced -7% body weight loss, and 3 x 3 mg/kg doxorubicin followed 6 h later by 3 x 12 mg/kg DOXO-EMCH produced a body weight gain of +2% as a clear indication of minimal systemic toxicity. In addition, cell culture experiments revealed additive to synergistic effects when MIA PaCa-2 cells were exposed to doxorubicin followed 6 h later to exposure of the albumin-bound form of DOXO-EMCH spanning a ratio of 1: 5 to 5: 1 (analyzed for synergistic, additive or antagonistic effects using the software program CalcuSyn (R)). This animal study demonstrates that the time-dependent schedule of an albumin-binding prodrug and a free drug has a critical influence on the overall tolerability. A combination of doxorubicin and DOXO-EMCH is currently being investigated in a phase Ib study. (C) 2012 Elsevier B. V. All rights reserved.