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Design of new oxazaphosphorine anticancer drugs
journal contributionposted on 2007-03-01, 00:00 authored by J Liang, M Huang, Wei DuanWei Duan, X Q Yu, S Zhou
The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, β-Dglucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a β-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)- bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.
JournalCurrent pharmaceutical design
Pagination963 - 978
PublisherBentham Science Publishers Ltd.
LocationHilversum, The Netherlands
Publication classificationC1 Refereed article in a scholarly journal
Copyright notice2007, Bentham Science Publishers Ltd.
oxazaphosphorinecyclophosphamideifosfamidetrofosfamideglufosfamidemafosfamideScience & TechnologyLife Sciences & BiomedicinePharmacology & PharmacyPHASE-II TRIALHIGH-DOSE CHEMOTHERAPYREGULATORY T-CELLSPERIPHERAL-BLOOD LYMPHOCYTESCHRONIC MYELOGENOUS LEUKEMIACOLONY-STIMULATING FACTORMETASTATIC BREAST-CANCERINTERSTRAND CROSS-LINKSTOTAL-BODY IRRADIATIONNON-HODGKIN-LYMPHOMA