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[0005] Doxorubicin is a compound known for many decades and used as DNA intercalator, and as such acts as topoisomerase inhibitor. Doxorubicin is employed as a chemotherapeutic drug for various cancers, and especially ovarian cancer, various sarcomas, and multiple myeloma. While at least some therapeutic effect can be achieved with doxorubicin, significant side effects are known, including fatigue, fever, vomiting, diarrhea, neutropenia, thrombocytopenia, and anemia. More serious side effects include severe myelosuppression, hepatic impairment, and cardiotoxicity. Indeed, doxorubicin has a black box warning for cardiotoxicity in the form of congestive heart failure indicated by significant decreases in left ventricular ejection fraction (LVEF). In view of this significant toxicity, the allowable maximum cumulative lifetime dose of doxorubicin is 550 mg/m .
0043] Based on the results above, the inventors investigated whether even higher total cumulative doses of aldoxorubicin could be tolerated. To that end, patients were administered total cumulative dosages of up to 3,000 mg/m , up to 4,000 mg/m , up to 5,000 mg/m , up to 6,000 mg/m2, up to 7,000 mg/m2, up to 8,000 mg/m2, up to 9,000 mg/m2, up to 10,000 mg/m2, up to 11,000 mg/m2, up to 12,000 mg/m2, up to 13,000 mg/m2, up to 14,000 mg/m2, and even higher. Remarkably, even doses of 14,000 mg/m were tolerated without any significant effect on cardiotoxicity and/or LVEF. As described herein, cardiotoxicity may be monitored by monitoring the level of metabolite doxorubicinol in the cardiac cells. Suitable cumulative dosages of aldoxorubicin include those that will not adversely affect LVEF. As such, LVEF of patients receiving aldoxorubicin will typically be in the range of 55% to 70%. Thus, in some embodiments, the patients may have LVEF of 55%-60%, or 60%-65%, or 65%-70%. Less preferably, aldoxorubicin may be administered to the patient until reaching a slightly lower than normal LVEF, say between 50%-54%, or 45%-50%, or 40%-45%.
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