ABSTRACT
PURPOSE: Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O'Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)(2) system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. METHODS: The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. RESULTS: Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. CONCLUSION: These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , DNA Damage/drug effects , DNA, Neoplasm/drug effects , Lung Neoplasms/drug therapy , Altretamine/administration & dosage , Altretamine/pharmacology , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/pharmacology , Apoptosis/drug effects , Carcinoma/genetics , Drug Synergism , Female , Lung Neoplasms/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/pharmacology , Random Allocation , Sesquiterpenes/administration & dosage , Sesquiterpenes/pharmacology , Transcription, Genetic/drug effects , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Enzyme Inhibitors/administration & dosage , Fluorouracil/administration & dosage , Sesquiterpenes/administration & dosage , Animals , Cell Line, Tumor , Deoxycytidine/administration & dosage , Drug Synergism , Female , Humans , Lung Neoplasms/drug therapy , Mice , Mice, Inbred BALB C , Random Allocation , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
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.