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MGI PHARMA, Inc., Minnetonka, Minnesota 55343-9667 [J. R. M., C. C. M.]; Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas 78245-3217 [D. L. D., G. L. M., S-F. C., D. D. V. H.]; and Department of Pathology, College of Medicine [M. J. K.] and Department of Chemistry [T. C. M.], University of California-San Diego, La Jolla, California 92093-0506
6-Hydroxymethylacylfulvene (HMAF; MGI 114) is a novel semisynthetic antitumor agent derived from the sesquiterpene mushroom toxin illudin S. In vitro cytotoxicity determinations produced IC50 concentrations (concentrations required for 50% inhibition of growth) ranging from 160 nM in sensitive MCF-7 human mammary carcinoma cells to 17 µM in relatively insensitive murine B16 melanoma cells. In vivo antitumor activity was consistent with in vitro sensitivity. HMAF was very effective in human tumor xenograft models, including MX-1 breast carcinoma, MV522 lung adenocarcinoma, and HT-29 colon carcinoma, but not murine B16 melanoma or P388 leukemia. Excellent responses were observed in animals bearing 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 administered i.v. HMAF. Extensive tumor shrinkage was also observed with MV522, and significant tumor growth inhibition was obtained with HT-29 when animals received 5 daily i.p. doses ranging from 3.75 to 7.5 mg/kg. Complete regressions were also observed in individual animals with MV522 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 trials.
1 To whom requests for reprints should be addressed, at MGI PHARMA, Inc., Opus Center, Suite 300E, 9900 Bren Road East, Minnetonka, MN 55343-9667.
Received 7/22/96. Accepted 11/14/96.
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