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.
Supported by funds provided by the cigarette and tobacco tax fund of the State of California through the Tobacco-related Disease Research Program of the University of California Award 4RT-0226 (to M. J. K.) and by funds provided by MGI Pharma Company, Minneapolis, Minnesota (to M. J. K. and T. C. M.).