Efficacy of Acylfulvene Illudin analogues against a metastatic lung carcinoma MV522 xenograft nonresponsive to traditional anticancer agents: retention of activity against various mdr phenotypes and unusual cytotoxicity against ERCC2 and ERCC3 DNA helicase-deficient cells.
Four second-generation Illudin analogues were synthesized and tested for antitumor activity using a metastatic lung carcinoma xenograft model resistant to conventional antitumor agents. One analogue, the parent illudofulvene-derivative called Acylfulvene, inhibited xenograft primary tumor growth and prolonged life span of tumor-bearing animals when administered i.p. or i.v. The efficacy of Acylfulvene exceeded that of mitomycin C, cisplatin, paclitaxol, the parent compound Illudin S, and an earlier analogue, dehydroilludin M. Promising features of this new analogue are: (a) the retention of in vitro activity against a variety of mdr tumor phenotypes including gp170+, gp150+, GSHTR-Pi, topoisomerase I, and topoisomerase II mutants; and (b) an apparent selective cytotoxicity toward cells deficient in either ERCC2 or ERCC3 DNA helicase activity.
Kelner
M J
MJ
Department of Pathology, UCSD Medical Center 92103-8320, USA.
McMorris
T C
TC
Estes
L
L
Starr
R J
RJ
Rutherford
M
M
Montoya
M
M
Samson
K M
KM
Taetle
R
R
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004265:DNA Helicases / Q000172:deficiency*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D051759:Xeroderma Pigmentosum Group D Protein
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D011506:Proteins; D012717:Sesquiterpenes; D014157:Transcription Factors; C078672:hay protein, Drosophila; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497293:Ercc2 protein, mouse