EFFICACY OF ACYLFULVENE ILLUDIN ANALOGS 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 f or antitumor activity using a metastatic lung carcinoma xenograft mode l resistant to conventional antitumor agents. One analogue, the parent illudofulvene-derivative called Acylfulvene, inhibited xenograft prim ary tumor growth and prolonged Life span of tumor-bearing animals when administered i.p. or i.v. The efficacy of Acylfulvene exceeded that o f mitomycin C, cisplatin, paclitaxol, the parent compound Illudin S, a nd an earlier analogue, dehydroilludin M. Promising features of this n ew analogue are: (a) the retention of in vitro activity against a vari ety of mdr tumor phenotypes including gp170+, gp150+, GSHTR-Pi, topois omerase I, and topoisomerase II mutants; and (b) an apparent selective cytotoxicity toward cells deficient in either ERCC2 or ERCC3 DNA heli case activity.