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      4-Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a promising new candidate for chemotherapeutic treatment of osteosarcoma patients.

      European Journal of Cancer
      Antibiotics, Antineoplastic, pharmacokinetics, therapeutic use, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, drug effects, Bone Neoplasms, drug therapy, Cell Cycle, Cell Line, Tumor, Daunorubicin, analogs & derivatives, Doxorubicin, administration & dosage, Drug Interactions, Drug Screening Assays, Antitumor, Humans, Osteosarcoma

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          The effectiveness of the alkycycline 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548, ladirubicin), a new drug with high antitumour activity against a broad range of neoplasms, was evaluated by using a panel of 32 human osteosarcoma cell lines, including cell lines resistant to doxorubicin, methotrexate, or cisplatin. PNU-159548 resulted to be highly active in all cell lines. No cross-resistance was found with conventional drugs, being PNU-159548 active also in cells resistant to doxorubicin and with a multidrug resistance phenotype (associated with MDR1 gene/P-glycoprotein overexpression), as well as in cells resistant to methotrexate or to cisplatin. Analysis of drug-drug interactions showed that PNU-159548 could be successfully used in combination with all the most important drugs currently used in OS chemotherapy. In fact, the simultaneous administration of PNU-159548 and doxorubicin, methotrexate, or cisplatin produced mostly additive or synergistic effects. Sequential exposure to PNU-159548 followed immediately by doxorubicin, methotrexate, or cisplatin was the most effective sequence of administration, invariably resulting in additive or synergistic effects in both drug-sensitive and drug-resistant osteosarcoma cell lines. In conclusion, the high in vitro effectiveness, the absence of cross-resistance with doxorubicin, methotrexate, or cisplatin and the possibility to be successfully used in combination with these drugs indicate PNU-159548 as a promising candidate to be considered for planning new therapeutic regimens for osteosarcoma patients, who show a decreased response to conventional chemotherapy.

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