Marked activity of irofulven toward human carcinoma cells: comparison with cisplatin and ecteinascidin.
OBJECTIVE
To characterize the activities of irofulven, a novelanticancer agent derived from the mushroom natural productilludin S toward human cancer cells.


METHODS
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.
Poindessous
Virginie
V
Laboratory 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.
Koeppel
Florence
F
Raymond
Eric
E
Comisso
Martine
M
Waters
Stephen J
SJ
Larsen
Annette K
AK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003470:Culture Media / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008956:Models, Chemical; D010936:Plant Extracts / Q000494:pharmacology; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D000077606:Trabectedin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D003470:Culture Media; D004149:Dioxoles; D007546:Isoquinolines; D010936:Plant Extracts; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; C102714:irofulven; D005982:Glutathione Transferase; D020741:rho GTP-Binding Proteins; D005721:Glutamate-Cysteine Ligase; C008105:illudin S; D000077606:Trabectedin; D002945:Cisplatin