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.

Improved Efficacy of Acylfulvene in Colon Cancer Cells When Combined with a Nuclear Excision Repair Inhibitor

“…When NER was inhibited, the cells were 2-fold more sensitive toward AF, indicating that when the cell cannot remove the AF-adduct, cytotoxicity is promoted. This observation is in agreement with previous studies where it was demonstrated that NER-deficient cells were more sensitive to AF, suggesting that the associated DNA damage is an NER substrate. ,, Furthermore, in a previous screening study, UCN-01 was among a group of miscellaneous compounds that showed evidence of a synergistic effect with HMAF . These data are consistent with the notion that when treating cancer cells with a combination of UCN-01 and AF, the concentration of the cytotoxic drug can be lower to achieve the same effect as when treating solely with AF.…”

“…10,23,24 Furthermore, in a previous screening study, UCN-01 was amongst a group of miscellaneous compounds that showed evidence of a synergistic effect with HMAF. 34 These data are consistent with the notion that when treating cancer cells with a combination of UCN-01 and AF, the concentration of cytotoxic drug can be lower to achieve the same effect as when treating solely with AF. Translated to therapeutic applications, this property might result in fewer side-effects.…”

Targeting the DNA Damage Response in Cancer

“…Thus, the cytotoxicity of these drugs depends on an intact DNA repair pathway. Irofulven has also been shown to synergize with cisplatin − and gemcitabine , both in in vitro and in vivo tumor models. Thus, this class of drugs triggers a TCR response leading to the induction of DNA damage, but whether the actions of these drugs are tumor-selective needs further evaluation.…”

Enhanced Anticancer Activity of Gemcitabine in Combination with Noscapine via Antiangiogenic and Apoptotic Pathway against Non-Small Cell Lung Cancer

“…Gemcitabine (Gem) is a pyrimidine nucleoside antimetabolite agent which is active against variety of human malignancies, including NSCLC with a favorable toxicity profile [6], [7]. Several researchers have studied the combination of Gem and cisplatin, topotecan, protease inhibitors, and ginsenoside Rg3 for the treatment of lung cancer [8], [9], [10], [11], [12]and reported enhanced anticancer effects [8], [9], [10], [11], [12], [13].…”