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.
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. 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%.
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 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%|
|Gastrointestinal system||Nausea and vomiting||Over 50%|
|Central nervous system||Encephalopathy||15%|
|Endocrine and metabolic systems||Metabolic acidosis||30%|
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