Basic studies on combination of new hypoxic cell sensitizers and intraoperative radiotherapy for unresectable pancreatic cancer

我们研究了人胰腺癌细胞裸鼠移植瘤的放射敏感性和乏氧分数，以及一种新的乏氧细胞放射增敏剂doranidazole对它们的疗效。虽然在日本正在进行一项临床研究，多拉硝唑结合术中放疗局部不可切除的胰腺癌，很少有数据已经报道了这些issues.In体外，四个建立的人胰腺癌细胞系（SUIT-2，PANC-1，MIA PaCa-2和BxPC-3）和小鼠SCCVII肿瘤细胞（比较）。在有氧或低氧照射之前和期间，用0.4或1 mM多拉硝唑处理这些细胞45分钟，并使用殖民地测定法测定细胞存活。在体内，Balb/c裸小鼠背部携带胰腺癌（约200 mg），在颈椎脱位后接受全身照射，无需物理约束或麻醉，或静脉注射100 mg/kg（0.4 mmol/kg） ...更多信息 r 250 mg/kg（1 mmol/kg）多拉硝唑。照射后，进行体内-体外测定。乏氧分数通过配对存活曲线法估计。关于体外放射敏感性，四种胰腺癌细胞系没有共同的特征。在体外实验中，多拉硝唑在有氧条件下对胰腺癌细胞无增敏作用，但在低氧条件下，0.4mM和1 mM时的增敏比（SER）分别为1.25-1.3和1.4-1.55。这些Sers类似于在SCCVII细胞中获得的那些。在体内，SUIT-2中的缺氧分数为20%（95% CI，11-38%），PANC-1中为14%（6.5-28%），MIA PaCa-2中为10%（5.9-16%），BxPC-3肿瘤中为27%（15-46%）。多拉硝唑的SER在100 mg/kg剂量下为1.15-1.3，在250 mg/kg剂量下为1.35-1.45。总之，四种异种移植胰腺癌的缺氧分数为10-27%（平均值：18%）。这些结果可能表明，使用缺氧细胞增敏剂是合理的术中放射治疗不可切除的胰腺癌。多拉硝唑对所有胰腺癌细胞株均有一定的体内外作用，但其Sers率均不高。应在未来的临床研究中研究剂量递增。少

We investigated the radiosensitivity and hypoxic fraction of human pancreatic cancer cells xenografted in nude mice, and the efficacy of a new hypoxic cell radiosensitizer doranidazole against them. Although a clinical study of doranidazole in combination with intraoperative radiotherapy is ongoing in Japan for localized unresectable pancreatic cancer, few data have been reported on these issues.In vitro, four established human pancreatic cancer cell lines (SUIT-2, PANC-1, MIA PaCa-2 and BxPC-3) and murine SCCVII tumor cells (for comparison) were used. These cells were treated with 0.4 or 1 mM doranidazole for 45 min prior to and during aerobic or hypoxic irradiation, and the cell survival was determined using the colony assay. In vivo, Balb/c nude mice bearing the pancreatic cancers (about 200 mg) on their backs received whole-body irradiation either after cervical dislocation, without physical restraint or anesthesia, or 20 min after intravenous injection of 100 mg/kg (0.4 mmol/kg) o … More r 250 mg/kg (1 mmol/kg) of doranidazole. Following irradiation, the in vivo-in vitro assay was performed. The hypoxic fraction was estimated by the paired survival curve method.Regarding in vitro radiosensitivity, there were no characteristics common to the four pancreatic cancer cell lines. In vitro, doranidazole had no sensitizing effect under aerobic conditions, but under hypoxic conditions, its sensitizer enhancement ratio (SER) was 1.25-1.3 at 0.4 mM and 1.4-1.55 at 1 mM against the four pancreatic cancer cell lines. These SERs were similar to those obtained in SCCVII cells. In vivo, the hypoxic fraction was 20% (95% CI, 11-38%) in SUIT-2, 14% (6.5-28%) in PANC-1, 10% (5.9-16%) in MIA PaCa-2, and 27% (15-46%) in BxPC-3 tumors. The SER of doranidazole was 1.15-1.3 at the dose of 100 mg/kg and 1.35-1.45 at 250 mg/kg.In summary, the four xenografted pancreatic cancers had hypoxic fractions of 10-27% (mean : 18%). These results might suggest that the use of a hypoxic cell sensitizer is reasonable in intraoperative radiotherapy for unresectable pancreatic cancer. Doranidazole had definite in vitro and in vivo effects on all pancreatic cancer cell lines, but the SERs were not high enough. Dose escalation should be investigated in future clinical studies. Less