OncoRay - National Center for Radiation Research in Oncology, Dept. of Radiation Oncology, Experimental Radiotherapy, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
Strahlenther Onkol. 2012 May;188(5):431-7. doi: 10.1007/s00066-011-0054-3. Epub 2012 Feb 16.
High pretreatment tumor lactate content is associated with poor outcome after fractionated irradiation in human squamous cell carcinoma (hSCC) xenografts. Therefore, decreasing lactate content might be a promising approach for increasing tumor radiosensitivity. As the basis for such experiments, the effects of the biochemical inhibitors pyruvate dehydrogenase kinase dichloroacetate (DCA), lactate dehydrogenase oxamate, and monocarboxylic acid transporter-1 α-cyano-4-hydroxycinnamate (CHC) on tumor micromilieu and growth were investigated.
Oxygen consumption (OCR) and extracellular acidification rates (ECAR) were measured in FaDu and UT-SCC-5 hSCC in response to DCA in vitro. Mice bearing FaDu, UT-SCC-5, and WiDr colorectal adenocarcinoma received either DCA in drinking water or DCA injected twice a day, or CHC injected daily. WiDr was also treated daily with oxamate. FaDu and UT-SCC-5 were either excised 8 days after treatment for histology or tumor growth was monitored. WiDr tumors were excised at 8 mm. Effect of inhibitors on ATP, lactate, hypoxia, and Ki67 labeling index (LI) was evaluated.
DCA increased OCR and decreased ECAR in vitro. None of the treatments with inhibitors significantly changed lactate content, hypoxia levels, and Ki67 LI in the three tumor lines in vivo. ATP concentration significantly decreased after only daily twice injections of DCA in FaDu accompanied by a significant increase in necrotic fraction. Tumor growth was not affected by any of the treatments.
Overall, tumor micromilieu and tumor growth could not be changed by glycolysis modifiers in the three tumor cell lines in vivo. Further studies are necessary to explore the impact of metabolic targets on radiation response.
高预处理肿瘤乳酸含量与人类鳞状细胞癌（hSCC）异种移植分次照射后的不良预后相关。因此，降低乳酸含量可能是提高肿瘤放射敏感性的一种有前途的方法。作为此类实验的基础，研究了生化抑制剂丙酮酸脱氢酶激酶二氯乙酸（DCA）、乳酸脱氢酶氧代甲酸盐和单羧酸转运蛋白-1α-氰基-4-羟基肉桂酸（CHC）对肿瘤微环境和生长的影响。
在 FaDu 和 UT-SCC-5 hSCC 中，体外测量 DCA 对氧消耗（OCR）和细胞外酸化率（ECAR）的影响。携带 FaDu、UT-SCC-5 和 WiDr 结直肠腺癌的小鼠分别用 DCA 饮用水或 DCA 每日两次注射，或 CHC 每日注射。WiDr 也每日用氧代甲酸盐治疗。治疗 8 天后切除 FaDu 和 UT-SCC-5 进行组织学检查，或监测肿瘤生长。WiDr 肿瘤在 8mm 时切除。评估抑制剂对 ATP、乳酸、缺氧和 Ki67 标记指数（LI）的影响。
DCA 在体外增加 OCR 并降低 ECAR。三种肿瘤细胞系中，抑制剂治疗均未显著改变乳酸含量、缺氧水平和 Ki67 LI。仅 FaDu 中 DCA 每日两次注射后，ATP 浓度显著降低，同时坏死分数显著增加。肿瘤生长不受任何治疗的影响。
总的来说，在三种肿瘤细胞系中，糖酵解修饰物不能改变肿瘤微环境和肿瘤生长。需要进一步研究代谢靶点对辐射反应的影响。
