Removal of incorporated gemcitabine by DNA repair mechanisms may contribute to resistance to the agent in solid tumors. In a study reported in Journal of the National Cancer Institute, Raoof and colleagues found that radiofrequency-induced hyperthermia blocked repair of gemcitabine-stalled replication forks and thus improved gemcitabine antitumor activity.
The study showed that Mre11-mediated homologous recombination repair of gemcitabine-stalled replication forks was crucial to hepatocellular carcinoma cell survival. Mre11 was inhibited by an exonuclease inhibitor and by radiofrequency field-induced hyperthermia. In orthotopic mouse models of chemoresistant hepatocellular carcinoma, Hep3B tumor mass was significantly smaller with radiofrequency-induced hyperthermia plus gemcitabine vs gemcitabine alone (mean = 180 vs 661 mg, P = .0063).
The investigators concluded: “This study provides mechanistic understanding of homologous recombination inhibiting-strategies, such as noninvasive radiofrequency field-induced hyperthermia, to overcome resistance to gemcitabine in refractory human solid tumors.” ■
Raoof M, et al: J Natl Cancer Inst 106(8):dju183 2014.