Antitumor activity of irofulven monotherapy and in combination with mitoxantrone or docetaxel against human prostate cancer models.
BACKGROUND
Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114) is a novel antitumor agent currently undergoing clinical trials in hormone-refractory prostate cancer. This report examines the efficacy of irofulven alone or in combination with mitoxantrone or docetaxel against androgen-independent prostate cancer cell lines.


METHODS
To elucidate the activity of irofulven monotherapy and in combination, PC-3 and DU-145 cell lines were utilized in cellular viability assessments and tumor growth inhibition studies.


RESULTS
Viability assays with irofulven and mitoxantrone show additive to synergistic activity. Furthermore, irofulven and mitoxantrone in combination exhibit enhanced antitumor activity against PC-3 and DU-145 xenografts. Additive combination effects are also observed when irofulven and docetaxel were tested against PC-3 xenografts and curative activity (8/10 CR) is observed in DU-145 xenografts.


CONCLUSIONS
These studies demonstrate that irofulven displays strong activity as monotherapy and in combination with mitoxantrone or docetaxel against androgen-independent prostate cancer in vitro and in vivo; thus, supporting the clinical investigation of irofulven against hormone-refractory prostate cancer.
Research and Development Department, MGI Pharma, Inc., Bloomington, Minnesota 55437, USA. evanlaar@mgipharma.com
Emily S
ES
Van Laar
Steven
S
Weitman
John R
JR
MacDonald
Stephen J
SJ
Waters
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; D043823:Taxoids; D000077143:Docetaxel; C102714:irofulven; D008942:Mitoxantrone