Efficacy of Acylfulvene Illudili 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 Cells1

Four second-generation Illuditi 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 Illudili S, and an earlier analogue, dehydroilludin M. Promising features of this new ana logue are: (a ) the retention of in vitro activity against a variety of mdr tumor phenotypes including gpl70+, gpl50+, GSHTR-Pi, topoisomerase I, and topoisomera.se II mutants; and i/»an apparent selective Cytotoxicity toward cells deficient in either ERCC2 or ERCC3 DNA helicase activity.