C. Geroni, D. Ballinari, A. Marsiglio
Nov 1, 2007
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Molecular Cancer Therapeutics
Abstract
A277 Nemorubicin (39-deamino-39-[2-(S)-methoxy-4-morpholinyl]doxorubicin hydrochloride) is a “non-conventional” anthracycline in clinical development for the intrahepatic artery chemotherapy of HCC. In Phase I/II studies as a single agent, nemorubicin has shown promising efficacy and fairly good tolerability. Based on the role of combination chemotherapy in cancer treatment, and its importance for the activity of newer therapies, the purpose of our study was to evaluate the antitumor effects of nemorubicin in combination with “classical” or “novel molecular-targeted” dugs currently used in the treatment of HCC, namely cisplatin (cDDP), mitomycin C (Mito-C), doxorubicin (DX) and bevacizumab (Avastin ® ). Combination studies were performed to exploit the ability of nemorubicin to overcome several mechanisms of drug resistance and the collateral sensitivity to different agents observed in nemorubicin-resistant cells. Results show that the sequential intravenous administration of nemorubicin (day 1,2) and cDDP (day 3) to mice bearing disseminated L1210 murine leukemia, yielded an increase in life span (ILS) that was significantly greater (p vs. 50 and 33%, for single agent nemorubicin and cDDP, respectively). Outstandingly, no increase in toxicity was observed after combined treatment with the two agents. Similarly, the combination of nemorubicin (day 1,2) with Mito-C (day 3) was synergistic against disseminated L1210 murine leukemia (ILS, 87% for the combination vs. 64 and 14% for single agent nemorubicin and Mito-C, respectively; p vs. both nemorubicin and Mito-C alone). Further, synergism of nemorubicin with DX in the L1210 disseminated leukemia model was observed when the drugs were given simultaneously on day 1,5, and 9 (ILS, 113% for the combination vs. 35% for both nemorubicin and DX alone; p vs. 7 and 4.7 days for single agent nemorubicin and bavacizumab, respectively). To support clinical development, preclinical combination studies were performed, further experiments are ongoing and data will be presented. A clear therapeutic gain was observed in preclinical settings combining nemorubicin with various drugs currently used in the clinics for the treatment of HCC. At present, a Phase I/II trial evaluating nemorubicin in combination with cDDP in HCC patients is ongoing in Europe.