EFFICACY OF HMAF (MGI-114) IN THE MV522 METASTATIC LUNG-CARCINOMA XENOGRAFT MODEL NONRESPONSIVE TO TRADITIONAL ANTICANCER AGENTS

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, resi stant to conventional anticancer agents. These illudin analogs prolong ed life span as compared to conventional agents, but did not induce co mplete remission of primary tumors. lit vitro screening studies identi fied a semisynthetic derivative, hydroxymethylacylfulvene (HMAF, MGI-1 14), with increased selective cytotoxicity towards carcinoma cells. Th e HMAF analog was markedly effective in the experimental MV522 metasta sizing lung carcinoma xenograft system, a model refractory to treatmen t with existing anticancer agents. Treatment with paclitaxel, doxorubi cin, or cisplatin failed to significantly inhibit primary tumor growth or prolong life span of MV522 tumor-bearing animals. Treatment with m itomycin C at the LD(20) increased life span in surviving animals up t o 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 agent s. These results support further evaluation of HMAF as a therapeutic a gent for treatment of solid tumors such as adenocarcinoma of the lung.