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Updated: Aug 22, 2026
In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
Published on: September 23, 2021
Irofulven cytotoxicity depends on transcription-coupled nucleotide excision repair and is correlated with XPG
Florence Koeppel1, Virginie Poindessous, Vladimir Lazar
1Group of Biology and Pharmacogenetics of Human Tumors, Centre National de la Recherche Scientifique, UMR 8113, Institut Gustave-Roussy, Villejuif, France.
Background:
Irofulven is a novel alkylating agent with promising clinical activity, particularly toward ovarian and hormone-refractory prostate cancers. To facilitate additional clinical development, we have aimed to identify biological markers associated with sensitivity to the compound.
Methods:
Fibroblasts derived from patients with xeroderma pigmentosum or Cockayne's syndrome along with a panel of 20 human cancer cell lines (eight different tumor types) were examined to establish the importance of nucleotide excision repair proteins in the sensitivity to irofulven.
Results:
Human cells deficient in nucleotide excision repair are up to 30-fold more sensitive to the cytotoxic effects of irofulven compared with repair-proficient controls, clearly indicating that nucleotide excision repair plays a crucial role in the sensitivity to the drug. Interestingly, our results show that irofulven-induced lesions are recognized by transcription-coupled repair but not by global genome repair. Another unique feature is the pronounced sensitivity of XPD and XPB helicase-deficient cells to the drug. Comparison of the IC50 values for irofulven, cisplatin, and ecteinascidin 743 with the expression levels of ERCC1, XPD, and XPG genes in different solid tumor cell lines shows no correlation between the expression levels of any of the three nucleotide excision repair proteins and the sensitivity to ecteinascidin 743. In contrast, expression of the XPG endonuclease was correlated with the cytotoxicity for irofulven and, to a lesser degree, for cisplatin. Importantly, XPG expression was also correlated with cellular nucleotide excision repair activity.
Conclusions:
Increasing evidence indicates that compromised nucleotide excision repair activity is frequent in several solid tumor types. The results presented here suggest that XPG expression in such tumors may be a useful marker to predict their sensitivity to irofulven.
Insights
Nucleotide excision repair (NER) significantly impacts sensitivity to the alkylating agent irofulven. XPG endonuclease expression may predict patient response in solid tumors with compromised NER.
Area of Science:
- Molecular oncology
- DNA repair mechanisms
- Cancer therapeutics
Background:
- Irofulven is a novel alkylating agent showing promise in ovarian and hormone-refractory prostate cancers.
- Identifying biomarkers for irofulven sensitivity is crucial for its clinical development.
Purpose of the Study:
- To investigate the role of nucleotide excision repair (NER) proteins in cellular sensitivity to irofulven.
- To identify potential biomarkers for predicting irofulven efficacy.
Main Methods:
- Assessed sensitivity to irofulven in fibroblasts from xeroderma pigmentosum and Cockayne's syndrome patients.
- Analyzed 20 human cancer cell lines (eight tumor types) for irofulven sensitivity.
- Correlated drug cytotoxicity (IC50 values) with gene expression levels of NER proteins (ERCC1, XPD, XPG).
Main Results:
- Cells deficient in NER were up to 30-fold more sensitive to irofulven, highlighting NER's critical role.
- Irofulven-induced lesions were recognized by transcription-coupled repair, not global genome repair.
- XPG endonuclease expression strongly correlated with irofulven cytotoxicity and cellular NER activity.
Conclusions:
- Compromised NER activity is common in various solid tumors.
- XPG expression may serve as a predictive biomarker for irofulven sensitivity in these tumors.
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