Diverging the anthracycline class of anti-cancer drugs for superior survival of acute myeloid leukemia patients
Qiao, X.; van der Zanden, S.; Li, X.; Tan, M.; Zhang, Y.; Song, J.-Y.; van Gelder, M.; Hamoen, F.; Janssen, L.; Zuur, C.; Pang, B.; van Tellingen, O.; Li, J.; Neefjes, J.
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The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxification of anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are now a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S.. To address this, we examined different clinically relevant anthracycline drugs with respect to a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. We show that different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical trials as it potently kills cancer cells, does not induce therapy-related malignancies or cardiotoxicity, and can be safely administered even after a maximum cumulative dose of either ida- or doxorubicin has been reached. Retrospective analysis of aclarubicin used in second-line treatment of relapsed/refractory AML patients showed similar survival effects to its use in first line, leading to an almost 25% increase in 5-year overall survival. Considering individual anthracyclines as different drugs provides new treatment options that strongly improve survival of cancer patients while limiting the toxic side-effects. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/23298950v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@4d6483org.highwire.dtl.DTLVardef@101d8b7org.highwire.dtl.DTLVardef@3adf1aorg.highwire.dtl.DTLVardef@10d2c49_HPS_FORMAT_FIGEXP M_FIG C_FIG
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