PRECLINICAL ANTITUMOR-ACTIVITY OF 6-HYDROXYMETHYLACYLFULVENE, A SEMISYNTHETIC DERIVATIVE OF THE MUSHROOM TOXIN ILLUDIN-S

6-Hydroxymethylacylfulvene (HMAF; MGI 114)B a novel semisynthetic anti tumor agent derived from the sesquiterpene mushroom toxin illudin S. I n vitro cytotoxicity determinations produced IC50 concentrations (conc entrations required for 50% inhibition of growth) ranging from 160 nM in sensitive MCF-7 human mammary carcinoma cells to 17 mu M in relativ ely insensitive murine B16 melanoma cells, In vivo antitumor activity was consistent with in vitro sensitivity, HMAF was very effective in h uman tumor xenograft models, including MX-1 breast carcinoma, MV522 lu ng adenocarcinoma, and HT-29 colon carcinoma, but not murine B16 melan oma or P388 leukemia, Excellent responses were observed in animals bea ring MX-1 tumors administered i.v. or i.p. doses of 3-7.5 mg/kg daily for 5 days, with complete regression recorded in 29 of 30 animals admi nistered i.v. HMAF. Extensive tumor shrinkage was also observed with M V522, and significant tumor growth inhibition was obtained with HT-29 when animals received 5 daily i.p. doses ranging from 3.75 to 75 mg/kg , Complete regressions were also observed in individual animals with M V522 and HT-29. The excellent activity of HMAF in several human solid tumor xenografts, including the more refractory MV522 and HT-29 models , warrants the further investigation of this novel agent in clinical t rials.