Antitumor activity of MGI 114 (6-hydroxymethylacylfulvene, HMAF), a semisynthetic derivative of illudin S, against adult and pediatric human tumor colony-forming units

MGI 114 (6-hydroxymethylacylfulvene, HMAF) is a novel semisynthetic antitum or compound derived from the sesquiterpene mushroom toxin illudin S, Althou gh illudins did not demonstrate significant activity as antiproliferative a gents in tumor-bearing animals, several properties including its potent inh ibition of DNA synthesis and a unique interaction with DNA led to a structu re-activity-based synthetic effort to obtain analogs with improved therapeu tic potential. MGI 114 was selected for further development based on its an titumor activity in numerous preclinical tests. MGI 114 was evaluated again st adult and pediatric human tumors taken directly from cancer patients and cultured in a human tumor colony-forming assay (HTCFA) to assess the antit umor 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 a t concentrations of 0.001, 0.01, 0.1 and 1 mu g/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% we re 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 con centration-response relationship to both exposure duration with responses i ncreasing from below 10% at the lowest concentration to over 70% at the hig hest concentration, except for the pediatric tumors on the Ih exposure for which this relationship was less apparent. At the higher concentration test ed, MGI 114 displayed substantial antiproliferative effects in the range of 70% against tumor specimens resistant to classic cytotoxic agents includin g irinotecan, paclitaxel, 5-fluorouracil, cisplatin, doxorubicin and cyclop hosphamide. These results demonstrate that MGI 114 exhibits a broad spectru m of antitumor activity against both adult and pediatric primary tumor colo ny-forming units in a concentration-dependent manner both at short and prol onged exposure duration. The substantial in vitro activity of MGI 114 at co ncentrations achievable in clinical trials, together with its activity agai nst tumors resistant to classic standard cytotoxic drugs, justifies the fur ther clinical evaluation of this unique agent, [(C) 1999 Lippincott William s & Wilkins.].