title: Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil.
abstract: The novel agent Irofulven (HMAF, NSC 683863) has demonstrated significant antitumor activity against solid tumors in various xenograft models and human clinical trials. The antitumor potential of combining irofulven with 72 different anti-metabolite, enzyme inhibiting, and miscellaneous agents was investigated in this study. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with these different agents. Irofulven in combination with select anti-metabolites, notably cytidine or adenine-derived agents, displayed strong synergistic activity in both in vitro and in vivo studies. Agents demonstrating strong synergistic interaction with irofulven included gemcitabine, cyclocytidine, cytarabine, fludarabine phosphate, cladribine, and 5-fluorouracil. Other anti-metabolites, enzyme inhibitors, and a variety of miscellaneous agents failed to interact beneficially when administered in combination with irofulven. The therapeutic activity of irofulven is enhanced considerably when irofulven is combined with select anti-metabolite agents, and further clinical evaluation of these combinations is warranted. The synergistic interaction with these combinations may stem from a variety of actions including inhibition of the nucleotide excision repair (NER) pathway, topoisomerase I activity, and caspase-dependent and independent induction of apoptosis.
authors.affiliation: Department of Pathology, University of California, San Diego, USA. mkelner@ucsd.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelner
authors.forename: Trevor C
authors.initials: TC
authors.lastname: McMorris
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Rojas
authors.forename: Leita A
authors.initials: LA
authors.lastname: Estes
authors.forename: Pharnuk
authors.initials: P
authors.lastname: Suthipinijtham
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D012717:Sesquiterpenes / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D012717:Sesquiterpenes; D003841:Deoxycytidine; C102714:irofulven; D005472:Fluorouracil; D000093542:Gemcitabine