Enhanced antitumor activity of irofulven in combination with antimitotic agents.
The aim of this study was to determine the antitumor activity of irofulven when administered in combination with a variety of antimitotic agents. Irofulven in combination with either paclitaxel or docetaxel demonstrated synergistic activity in both the in vitro and in vivo studies. The majority of xenograft bearing animals that received suboptimal (< MTD) doses of irofulven and a taxane demonstrated complete cures. In contrast, in vitro studies produced either an additive or an antagonistic effect when irofulven was combined with other antimitotic agents such as vinca alkaloids, rhizoxin, s-trityl cysteine, or allocolchicine. Xenograft studies of irofulven and vinca alkaloids reflected in vitro results, as the tumor response in combination treated animals was less than the response in irofulven (monotherapy) treated animals. These results indicate that the therapeutic activity of irofulven is enhanced when combined with taxanes, and warrant further evaluation of these combinations.
Department of Pathology, University of California, San Diego 92103, USA. mkelner@ucsd.edu
Michael J
MJ
Kelner
Trevor C
TC
McMorris
Rafael J
RJ
Rojas
Nicole A
NA
Trani
Tami R
TR
Velasco
Leita A
LA
Estes
Pharnuk
P
Suthipinijtham
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D007783:Lactones / Q000627:therapeutic use; D018942:Macrolides; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012717:Sesquiterpenes / Q000494:pharmacology*; D043823:Taxoids; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014748:Vinca Alkaloids / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D007783:Lactones; D018942:Macrolides; D012717:Sesquiterpenes; D043823:Taxoids; D014404:Tubulin; D014748:Vinca Alkaloids; C080625:taxane; C003724:3-tritylthio-L-alanine; C032782:allocolchicine; C102714:irofulven; C041443:rhizoxin; D003545:Cysteine; D003078:Colchicine