MGI 114 (6-hydroxymethylacylfulvene, HMAF) is a novel semisynthetic antitumor compound derived from the
sesquiterpene mushroom toxin
illudin S. Although illudins did not demonstrate significant activity as antiproliferative agents in
tumor-bearing animals, several properties including its potent inhibition of
DNA synthesis and a unique interaction with
DNA led to a structure-activity-based synthetic effort to obtain analogs with improved therapeutic potential.
MGI 114 was selected for further development based on its antitumor activity in numerous preclinical tests.
MGI 114 was evaluated against adult and pediatric human
tumors taken directly from
cancer patients and cultured in a human
tumor colony-forming assay (HTCFA) to assess the antitumor spectra, concentration-response relationship, schedule dependence and activity of this agent against
tumors considered resistant to conventional anticancer drugs. Human
tumor colony-forming units were treated with HMAF at concentrations of 0.001, 0.01, 0.1 and 1 microg/ml, both as a 1 h exposure and as a continuous 14 day exposure. A response was scored if there was 50% or less colony survival. In vitro response rates in the range of 50-80% were observed against
tumor colony-forming units originating from
carcinomas of the colon, kidney, breast,
lung cancer, ovary and
melanoma.
MGI 114 also demonstrated antitumor activity against
neuroblastoma colony-forming units. Antitumor activity was not influenced by exposure time as demonstrated by the similar responses rates obtained with the 1 h and continuous exposure at all concentrations tested. However, there was a significant positive concentration-response relationship to both exposure duration with responses increasing from below 10% at the lowest concentration to over 70% at the highest concentration, except for the pediatric
tumors on the 1 h exposure for which this relationship was less apparent. At the higher concentration tested,
MGI 114 displayed substantial antiproliferative effects in the range of 70% against
tumor specimens resistant to classic
cytotoxic agents including
irinotecan,
paclitaxel,
5-fluorouracil,
cisplatin,
doxorubicin and
cyclophosphamide. These results demonstrate that
MGI 114 exhibits a broad spectrum of antitumor activity against both adult and pediatric primary
tumor colony-forming units in a concentration-dependent manner both at short and prolonged exposure duration. The substantial in vitro activity of
MGI 114 at concentrations achievable in clinical trials, together with its activity against
tumors resistant to classic standard cytotoxic drugs, justifies the further clinical evaluation of this unique agent.