Preclinical antitumor activity of 6-hydroxymethylacylfulvene, a semisynthetic derivative of the mushroom toxin illudin S.
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 microM 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.
MacDonald
J R
JR
MGI PHARMA, Inc., Minnetonka, Minnesota 55343-9667, USA.
Muscoplat
C C
CC
Dexter
D L
DL
Mangold
G L
GL
Chen
S F
SF
Kelner
M J
MJ
McMorris
T C
TC
Von Hoff
D D
DD
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D012717:Sesquiterpenes; C102714:irofulven