Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation.
OBJECTIVE
To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer.


METHODS
The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41°C or 43°C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm(3), mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences.


RESULTS
When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors.


CONCLUSIONS
Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy.
From the Department of Research, Institut Curie, Bat 11215 Georges Clémenceau, Orsay 91405, France (F.D., M.H., A.C., M.D.); CNRS, Unit UMR3347, Orsay, France (M.D.); INSERM, Unit U1021, Orsay, France (M.D.); DNA Therapeutics, Evry, France (F.D., A.C., J.S.S.); Department of Radiotherapy, Centre Jean Perrin, Clermont-Ferrand, France (J.B.); Department of Pathology, Institut Pasteur, Paris, France (M.H.); Muséum National d'Histoire Naturelle USM503, Paris, France (J.S.S.); Université Paris-Sud, Paris, France (M.D.); and Department of Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (A.D.).
Flavien
F
Devun
Julian
J
Biau
Michel
M
Huerre
Amélie
A
Croset
Jian-Sheng
JS
Sun
Alban
A
Denys
Marie
M
Dutreix
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D000818:Animals; D017115:Catheter Ablation; D015179:Colorectal Neoplasms / Q000473:pathology*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D006801:Humans; D006979:Hyperthermia, Induced; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary* / Q000601:surgery*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides