Design of new oxazaphosphorine anticancer drugs.
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, beta-D-glucosylisophosphoramide 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 beta-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.
Liang
Jun
J
Department of Pharmacology and Toxicology, Australian Institute of Chinese Medicine, Carlingford, New South Wales, Australia.
Huang
Min
M
Duan
Wei
W
Yu
Xue-Qing
XQ
Zhou
Shufeng
S
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D007928:Lethal Dose 50; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D010752:Phosphoramide Mustards / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; D010752:Phosphoramide Mustards