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.