Illudin analogs are cytotoxic to a variety of multidrug resistant cell lines, and display an unusual toxicity towards
DNA helicase-deficient cell lines. Earlier illudin analogs demonstrated efficacy in several xenograft models, including a metastatic MV522
lung cancer model, resistant to conventional
anticancer agents. These illudin analogs prolonged life span as compared to conventional agents, but did not induce complete remission of primary
tumors. In vitro screening studies identified a semisynthetic derivative, hydroxymethylacylfulvene (HMAF, MGI-114), with increased selective cytotoxicity towards
carcinoma cells. The HMAF analog was markedly effective in the experimental MV 522 metastasizing lung
carcinoma xenograft system, a model refractory to treatment with existing
anticancer agents. Treatment with
paclitaxel,
doxorubicin, or
cisplatin failed to significantly inhibit primary
tumor growth or prolong life span of MV522
tumor-bearing animals. Treatment with
mitomycin C at the LD20 increased life span in surviving animals up to 61% (p = 0.04). Treatment with HMAF induced primary
tumor regression in all animals and increased life span greater than 150% (p < 0.001). Thus, administration of HMAF inhibited development of lung
metastasis in a model refractory to treatment with conventional
anticancer agents. These results support further evaluation of HMAF as a therapeutic agent for treatment of solid
tumors such as
adenocarcinoma of the lung.