Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C

Irofulven (6-hydroxymethylacylfulvene, MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a toxin present in the Omphalotus mushroom. Irofulven has demonstrated activity against a broad range of solid tumors in both xenograft models and human trials. The potential application of administering irofulven in combination with aziridine-containing chemotherapeutic agents was evaluated in this study.

Human lung carcinoma MV522 cells and BALB/c athymic mice bearing the human lung carcinoma MV522 xenograft were used to evaluate the activity of irofulven in combination with aziridine-containing drugs.

Irofulven in combination with either thiotepa or mitomycin C demonstrated a strong synergistic (supraadditive) activity both in vitro and in vivo, that exceeded results obtained with monotherapy at the same or higher doses of these agents. The majority of xenograft-bearing animals that received subtoxic doses of irofulven, and either thiotepa or mitomycin C, demonstrated a complete cure. In contrast, there was no detectable synergistic activity between irofulven and other aziridine-containing drugs, including AZQ and thiotepa metabolites such as TEPA or AZD.

These results indicate that the therapeutic activity of irofulven is enhanced when combined with mitomycin C or thiotepa, and further evaluation of these combinations is therefore warranted.