Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide

Cancer Gene Ther. 2001 Mar;8(3):220-30. doi: 10.1038/sj.cgt.7700290.


Feline kidney cells were transfected with a vector overexpressing cytochrome P450 2B1 (CYP2B1). Transfected cells acquired a new specific biochemical activity, which could be demonstrated by a rapid CYP2B1 detection assay and showed selective sensitivity to the antitumorigenic prodrug ifosfamide (IFO). Further, the cell-killing effect was also mediated on nonmodified cells like feline kidney cells, mouse lymphoma, and human pancreatic cells in the vicinity of the CYP2B1-expressing cells due to the diffusible nature of the activated IFO metabolites. One of these, phosphoramide mustard, causes interstrand DNA cross-linking and it has been thought that the inability to repair this damage results in apoptosis. Surprisingly, our results clearly demonstrate a necrotic mechanism of IFO-induced cell death. This may have important implications for the activation of the immune system during CYP2B1/IFO suicide gene therapy of cancer.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Apoptosis*
  • Cats
  • Cell Line
  • Cells, Cultured
  • Cytochrome P-450 CYP2B1 / genetics*
  • Cytochrome P-450 CYP2B1 / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / ultrastructure
  • Flow Cytometry
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Ifosfamide / metabolism
  • Ifosfamide / therapeutic use*
  • Kidney / pathology*
  • Necrosis*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Prodrugs / metabolism
  • Prodrugs / therapeutic use*
  • Sensitivity and Specificity
  • Transfection / methods*
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Alkylating
  • Prodrugs
  • Cytochrome P-450 CYP2B1
  • Ifosfamide