title: Optimized anti-tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule.
abstract: Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti-tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti-tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti-tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols.
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Ehrhardt
authors.forename: David
authors.initials: D
authors.lastname: Schrembs
authors.forename: Christian
authors.initials: C
authors.lastname: Moritz
authors.forename: Franziska
authors.initials: F
authors.lastname: Wachter
authors.forename: Subrata
authors.initials: S
authors.lastname: Haldar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graubner
authors.forename: Michaela
authors.initials: M
authors.lastname: Nathrath
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000532:radiotherapy; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000532:radiotherapy; D015398:Signal Transduction / Q000187:drug effects; D014748:Vinca Alkaloids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D014748:Vinca Alkaloids; D004317:Doxorubicin