The objective of this study was to investigate the cytotoxic activity of
irofulven (HMAF,
MGI 114), a unique chemotherapeutic agent currently under clinical investigation, in various preclinical models of
ovarian cancer. Antiproliferative effects of
irofulven in
ovarian cancer cell lines and ovarian
tumor specimens were characterized in vitro using
sulforhodamine B and human
tumor colony-forming assays, respectively.
Irofulven demonstrated marked activity against a panel of ovarian tumor cell lines, including IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3, all of which exhibit various drug resistance mechanisms. In human
tumor cloning assays,
irofulven inhibited colony formation in surgically derived ovarian
tumors at concentrations as low as 0.001 micro g /ml and indicated superior activity in comparison with
paclitaxel when tested against the same
tumor specimens. The antitumor activity of
irofulven compared to that of
paclitaxel was also examined using the SK-OV-3 xenograft model. In mice bearing subcutaneously implanted SK-OV-3
tumors, treatment with
paclitaxel failed to inhibit
tumor growth; whereas mice treated with maximum tolerated doses of
irofulven had a 25% partial shrinkage rate, and the remaining animals had a mean
tumor growth inhibition of 82%. The potent activity of
irofulven against ovarian
tumors in vitro and in vivo supports the evaluation of its clinical activity in
ovarian cancer.