Ifosfamide is a parenterally administered alkylating agent similar to cyclophosphamide. The chemical name of it is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphospholane-2-oxide and used for a variety of cancers. The structure is shown in fig. 1.
Fig. 1 Structure of ifosfamide
Application in the treatment of cancer
Ifosfamide has been effectively employed in the treatment of multiple cancers, including testicular cancer, soft tissue sarcoma, osteosarcoma, bladder cancer, small cell lung cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, epithelial ovarian cancer, cervical carcinoma and germ cell carcinoma of the ovary[1]. Among all these cancers, the Food and Drug Administration (FDA) has approved ifosfamide only for testicular cancer. A study analyzed the therapy outcomes of 39 patients with testicular cancer who were treated with ifosfamide as a monotherapy from 1970-1977. The results showed that 16/39 patients (41%) were tumor-free after chemotherapy and operation and 6 of them survived for more than 5 years. This amounts to a curative rate of 15%[2].
Mechanism of action
Ifosfamide is an inactive compound that belongs to the class of oxazaphosphorine alkylating agents. It is metabolized in the liver by CYP450 enzymes to active metabolites (phosphoramide mustard derivatives and acrolein) that bind to DNA and inhibit DNA synthesis in two ways. First, these active metabolites cause cell damage and apoptosis by forming interstrand or intrastrand DNA crosslinks. Second, these active metabolites upregulate reactive oxygen species (ROS), resulting in irreparable DNA damage and the cessation of protein formation. More importantly, ifosfamide is cytotoxic, so its antitumor activity is stronger than other alkylating agents.
Side effects
Side effects of ifosfamide are dose-related and can be described based on the affected system.
Table 1. Side effects of ifosfamide and the occurring rate in different affected systems
Adverse Event
Edaravone (n = 184) %
Placebo (n = 184) %
Renal system
Hematuria (used alone)
90%
Cardiac system
Arrhythmia
Under 10%
Hepatic system
Elevated liver enzymes, hepatic vein-occlusive
-
Hematologic system
Leukopenia, anemia, and thrombocytopenia
30-50%
Dermatologic system
Alopecia
90%
Gastrointestinal system
Nausea and vomiting
Over 50%
Central nervous system
Encephalopathy
15%
Endocrine and metabolic systems
Metabolic acidosis
30%
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References
Buda, A., et al. Role of ifosfamide in cervical cancer: an overview. Oncology. 2003, 65(suppl 2): 63-66.
Hartlapp, J. H., Weißbach, L. Ifosfamide monotherapy in testicular cancer. Journal of Cancer Research and Clinical Oncology. 1986.
