Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C.
OBJECTIVE
Irofulven (6-hydroxymethylacylfulvene, MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a toxin present in the Omphalotus mushroom. Irofulven has demonstrated activity against a broad range of solid tumors in both xenograft models and human trials. The potential application of administering irofulven in combination with aziridine-containing chemotherapeutic agents was evaluated in this study.


METHODS
Human lung carcinoma MV522 cells and BALB/c athymic mice bearing the human lung carcinoma MV522 xenograft were used to evaluate the activity of irofulven in combination with aziridine-containing drugs.


RESULTS
Irofulven in combination with either thiotepa or mitomycin C demonstrated a strong synergistic (supraadditive) activity both in vitro and in vivo, that exceeded results obtained with monotherapy at the same or higher doses of these agents. The majority of xenograft-bearing animals that received subtoxic doses of irofulven, and either thiotepa or mitomycin C, demonstrated a complete cure. In contrast, there was no detectable synergistic activity between irofulven and other aziridine-containing drugs, including AZQ and thiotepa metabolites such as TEPA or AZD.


CONCLUSIONS
These results indicate that the therapeutic activity of irofulven is enhanced when combined with mitomycin C or thiotepa, and further evaluation of these combinations is therefore warranted.
Kelner
Michael J
MJ
Department of Pathology 8320, UCSD Medical Center, 200 West Arbor Drive, San Diego, CA 92103, USA. mkelner@ucsd.edu
McMorris
Trevor C
TC
Rojas
Rafael J
RJ
Trani
Nicole A
NA
Estes
Leita
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001388:Aziridines / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D012717:Sesquiterpenes / Q000627:therapeutic use*; D013852:Thiotepa / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D001388:Aziridines; D012717:Sesquiterpenes; D016685:Mitomycin; C033132:aziridine; C102714:irofulven; D013852:Thiotepa