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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Marked activity of irofulven toward human carcinoma cells: comparison with cisplatin and ecteinascidin
Virginie Poindessous1, Florence Koeppel, Eric Raymond
1Laboratory of Biology and Pharmacogenetics of Human Tumors, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Ecole Normale Supérieure, Cachan and Institut Gustave-Roussy, Villejuif 94805 cedex, France.
Purpose:
To characterize the activities of irofulven, a novelanticancer agent derived from the mushroom natural productilludin S toward human cancer cells.
Experimental Design:
We have determined the activity spectrum of irofulven toward a human tumor cell panel comprised of 10 different tumor types in comparison with cisplatin and ET-743. We have also evaluated the influence of major resistance mechanisms, such as expression of multidrug resistance-associated drug efflux pumps, cisplatin resistance, loss of p53 function, and absence of mismatch repair on the cytotoxic activity of irofulven.
Results:
The activity spectrum of irofulven is clearly different from that of ET-743 and cisplatin. Irofulven shows excellent cytotoxicity toward the majority of human carcinoma cell lines tested, but lesser activity toward sarcoma and leukemia cell lines. The cytotoxic activity of irofulven was particularly pronounced toward head and neck, non-small cell lung, colon, and ovary carcinoma cells, as well as toward malignant glioma cell lines. In addition, irofulven displayed good activity toward poorly differentiated, androgen-independent prostate cancer cells and cell lines expressing high levels of the detoxifying enzymes glutathione S-transferase and gamma-glutamyl cysteine synthetase. The cytotoxicity of irofulven was not affected by loss of p53 or mismatch repair function, and the drug was not a substrate for multidrug transporters, such as the P-glycoprotein and multidrug resistance protein 1.
Conclusions:
Irofulven has an unusual activity spectrum with strong activity toward tumor cells of epithelial origin. Furthermore, irofulven is not or only marginally affected by resistance mechanisms limiting the efficacy of other alkylating agents.
Insights
Irofulven, a novel anticancer agent, shows potent activity against epithelial-derived human cancers, including head and neck, lung, colon, and ovarian carcinomas. It is effective even when common drug resistance mechanisms are present.
Area of Science:
- Pharmacology
- Oncology
- Natural Products Chemistry
Background:
- Irofulven is a novel anticancer agent derived from illudin S, a natural product from mushrooms.
- Understanding its activity spectrum and resistance mechanisms is crucial for its clinical development.
Purpose of the Study:
- To characterize the activity spectrum of irofulven against human cancer cells.
- To evaluate the influence of major resistance mechanisms on irofulven's cytotoxic activity.
Main Methods:
- Determined irofulven's activity spectrum across a panel of 10 human tumor types.
- Compared irofulven's activity with cisplatin and ET-743.
- Assessed the impact of multidrug resistance pumps, cisplatin resistance, p53 function, and mismatch repair on irofulven's cytotoxicity.
Main Results:
- Irofulven exhibits a distinct activity spectrum compared to cisplatin and ET-743.
- Showed excellent cytotoxicity against most human carcinoma cell lines, particularly head and neck, non-small cell lung, colon, and ovary.
- Demonstrated good activity against androgen-independent prostate cancer and cell lines with high glutathione S-transferase and gamma-glutamyl cysteine synthetase levels.
- Cytotoxicity was unaffected by loss of p53 or mismatch repair.
- Irofulven is not a substrate for P-glycoprotein or multidrug resistance protein 1.
Conclusions:
- Irofulven possesses an unusual activity spectrum with potent efficacy against epithelial-derived tumors.
- Its effectiveness is not significantly limited by common resistance mechanisms that affect other alkylating agents.
