title: Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy.
abstract: The potential of EHT 6706, a novel tubulin-binding agent, was investigated in combination with ionizing radiation (IR) and with conventional cytotoxic chemotherapy agents. Cell proliferation, cell cycle, apoptosis and clonogenic assays were performed in five human cancer cell lines: H460 (non small cell lung carcinoma, NSCLC), HCT116 and HCT116 p53-/- (colorectal cancer), MDA-MB-231 (breast cancer), and MiaPaca2 cells (pancreatic cancer). The drug inhibited cell proliferation in all cell lines. This effect was associated with G2/M arrest and activation of apoptosis in a dose-dependent manner. The drug was then tested in combination with chemotherapy and IR in vitro. Effects on proliferation and clonogenic survival were analyzed. EHT 6706 treatment inhibited clonogenic survival synergistically with IR in H460 and MiaPaca2 cell lines. In the remaining cell lines, the effects of EHT 6706 and IR were additive. For H460 and MiaPaca2 cell lines, the highest effect was seen when cells were exposed for 20 h to EHT 6706 before being irradiated. EHT 6706 also exerted additive inhibition of proliferation when given in combination with conventional chemotherapy agents, such as oxaliplatin, cisplatin and gemcitabine in H460 and MiaPaca2 tumor cell lines. These data show that EHT 6706 could act synergistically with IR and additively with chemotherapy in tumor cell lines in vitro. This provides a good rationale to further assess EHT 6706 in combination protocols and confirm these effects in vivo.
authors.affiliation: INSERM U1030, Radiothérapie Moléculaire, Institut Gustave Roussy, Université Paris XI, Villejuif, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Clémenson
authors.forename: Cyrus
authors.initials: C
authors.lastname: Chargari
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Casagrande
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D011839:Radiation, Ionizing; D014404:Tubulin / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C579423:7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine; D000970:Antineoplastic Agents; D007546:Isoquinolines; D009944:Organoplatinum Compounds; D014404:Tubulin; D000077150:Oxaliplatin; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine