Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts.
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.
van Laar
E S
ES
MGI Pharma, Bloomington, MN 55437-3174, USA. evanlaar@mgipharma.com
Izbicka
E
E
Weitman
S
S
Medina-Gundrum
L
L
Macdonald
J R
JR
Waters
S J
SJ
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; C102714:irofulven