Activity of irofulven against human pancreatic carcinoma cell lines in vitro and in vivo.
BACKGROUND
Irofulven (MGI 114), a novel antitumor agent synthesized from the natural product illudin S, has a unique mechanism of action involving macromolecule adduct formation, S-phase arrest and induction of apoptosis.


METHODS
This study utilized MiaPaCa pancreatic xenografts to demonstrate irofulven antitumor activity using either a daily or intermittent dosing schedule. Additionally, irofulven and gemcitabine were tested in vitro and in vivo to assess the anticancer activity of the combination.


RESULTS
Both dosing regimens of irofulven demonstrated curative activity against the MiaPaCa xenografts. Similar activity of irofulven on the intermittent schedule was observed at lower total doses compared to the daily dosing schedule. Furthermore, enhanced antitumor activity was observed when irofulven and gemcitabine were combined compared to single agent activity.


CONCLUSIONS
These results support further clinical characterization of intermittent irofulven dosing schedules and suggest that irofulven combined with gemcitabine may have activity in patients with pancreatic tumors.
Van Laar
Emily S
ES
MGI Pharma, Inc., 5775 West Old Shakopee Road, Suite 100, Bloomington, MN 55437-3174, USA. emily.vanlaar@mgipharma.com
Roth
Stephanie
S
Weitman
Steven
S
MacDonald
John R
JR
Waters
Stephen J
SJ
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; D003841:Deoxycytidine; C102714:irofulven; D000093542:Gemcitabine