晚期食管贲门癌综合治疗的研究

对50例晚期食管贲门癌包括伴有锁骨上淋巴结已有转移的病人,以手术切除为主,术后辅以化疗、放疗行综合性治疗。每例病人用卡铂200mg+5％葡萄糖液500ml静滴,每日1次,3天为一疗程,每月1次×3疗程。有癌残留或附近脏器有癌受侵润,切除不彻底者给予常规放疗,放疗剂量为40～70Gy。手术并发症7例:胸内吻合口瘘1例,颈部吻合口小瘘1例,呼吸衰竭2例,死亡率为4％,原因:1例为吻合口瘘感染导致主动脉破裂大出血,另1例呼吸衰竭死亡。近期随访结果:本组48例,死亡18例,死亡原因绝大多数是远处转移或复发。术后半年内死亡4例,1年内死亡7例,2年内死亡7例,总死亡率40％,2年内近期存活率63.3％。     

Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR

DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.