Illudins are a novel class of agents with a chemical structure entirely different from current chemotherapeutic agents. A new semisynthetic derivative,
MGI 114 (NSC 683,863, 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
paclitaxel, 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
paclitaxel,
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.