Efficacy of MGI 114 (6-hydroxymethylacylfulvene, HIMAF) against the mdr1/gp170 Metastatic MV522 lung carcinoma xenograft

Illudins are a novel class of agents with a chemical structure entirely different from current chemotherapeutic agents. A new semisynthetic derivative, MGI 114 (NSC 683863, 6-hydroxymethyl-acylfulvene, HMAF), is markedly effective in a variety of lung, breast and colon carcinoma xenograft models. This analogue, MGI 114, is currently in phase I human clinical trials, and is scheduled for two different phase II trials. To determine if MGI 114 could be effective in vivo against mdr tumour cells, we generated an mdr1/gp170-positive clone of the metastatic MV522 human lung carcinoma line by transfecting a eukaryotic expression vector containing the cDNA encoding for the human gp170 protein. This MV522/mdr1 daughter line retained the metastatic ability of parental cells. The parental MV522 xenograft is mildly responsive in vivo to mitomycin C and paciltaxel, as evidenced by partial tumour growth inhibition and a small increase in Life span, whereas MV522/mdr1 xenografts were resistant to these agents. In contrast to mitomycin C and paciltaxel, MGI 114 produced xenograft tumour regressions in 32 of 32 animals and completely eliminated tumours in more than 30% of MV522/mdr1 tumour-bearing mice. Thus, MGI 114 should be effective in vivo against mdr1/gp170-positive tumours. (C) 1998 Elsevier Science Ltd. All rights reserved.