Radiation and hyperthermia increases B-lapachone (B-lap) cytotoxicity

辐射和热疗会增加 B-拉帕酮 (B-lap) 细胞毒性

• 批准号: 7753901
• 负责人: Chang Won Song
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753901
• 关键词: 1-naphthol; Antineoplastic Agents; Apoptosis; Back; Biological Factors; Calpain; Cell Cycle Checkpoint; Cell Death; Cells; Clinical Trials; Effectiveness; Electrons; Experimental Neoplasms; Fever; Futile Cycling; Hand; Heat-Shock Response; Heating; Human; Hydroquinones; In Vitro; Induced Hyperthermia; Ionizing radiation; Leg; Malignant Neoplasms; Mediating; Mediation; Metabolism; Mitochondria; Mitomycins; Molecular; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NADH; NQO1 gene; Naphthols; Normal tissue morphology; Oxidoreductase; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Pyrans; Quinones; Radiation; Radiation Tolerance; Radiation therapy; Regimen; Relative (related person); Reporting; Role; Safety; Source; South America; T-Lymphocyte; Temperature; Time; Toxic effect; Treatment Protocols; Trees; Up-Regulation; base; cancer cell; cancer therapy; cell killing; chemotherapy; cytochrome c; cytotoxicity; hydroquinone; in vivo; irradiation; killings; neoplastic cell; repaired; response; tumor

DESCRIPTION (provided by applicant): p-Lapachone(p-Lap)(3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) is an experimental anti-cancer drug originally obtained from Lapacho trees. P-Lap causes cell death in a variety of human cancer cells. Phase I and II clinical trials to investigate the safety and effectiveness of 3-lap used alone or in combination with other chemotherapy drugs are underway elsewhere. These clinical trials are based on the hypothesis that p-lap kills cancer cells by activating cell cycle checkpoints. On the other hand, our hypothesis is that bioactivation of p-lap through mediation of NAD(P)H:quinone oxidoreductase (NQ01) induces cascade of molecular changes in cells leading to cell death. Therefore, the cytotoxicity of p-lap is closely related to the activity of cellular NQO1 level. Importantly, NQ01 activity in many human tumors is as much as 50 times greater than that in adjacent normal tissues indicating that p-lap may cause greater damage in tumors relative to normal tissues. Moreover, ionizing radiation (IR) causes a long-lasting elevation of NQO1 activity in cancer cells and, thus, IR and p-lap synergistically react in killing cancer cells. We have recently discovered that hyperthermia at clinically achievable temperatures, e.g. <42oC, also causes a long-lasting elevation of NQO1 activity in cancer cells, thereby potentiating the response of cancer cells to p-lap. We hypothesize that established tumor treatment regimens such as radiotherapy and hyperthermia can potentiate the p-lap cytotoxicity towards tumors by increasing NQO1 activity in the tumor cells. The overall aim of the present proposal is to develop effective regimens to selectively enhance the tumor response to p-lap by elevating NQO1 activity in the tumor utilizing radiotherapy and hyperthermia. Specific aims are (1) Determine the effect of IR on the NQO1 level and p-lap sensitivity of cancer cells, (2) Determine the effect of hyperthermia alone or in combination with IR on the NQ01 level and p-lap sensitivity of cancer cells, (3) Elucidate the response of tumors in vivo to P-lap with IR and hyperthermia individually and combined and (4) Delineate cellular and molecular mechanisms of IR- and hyperthermia-induced elevation of NQO1.

描述（由申请人提供）：对拉帕酮（p-Lap）（3，4-二氢-2，2-二甲基-2H-萘酚[1，2-B]吡喃-5，6-二酮）是一种最初从拉帕乔树中获得的实验性抗癌药物。P-Lap导致多种人类癌细胞的细胞死亡。其他地区正在进行I期和II期临床试验，以研究3-lap单独使用或与其他化疗药物联合使用的安全性和有效性。这些临床试验基于p-lap通过激活细胞周期检查点杀死癌细胞的假设。另一方面，我们的假设是通过NAD（P）H：醌氧化还原酶（NQ 01）介导的p-lap的生物活化诱导细胞中的级联分子变化，导致细胞死亡。因此，p-lap的细胞毒性与细胞内NQO 1活性水平密切相关。重要的是，许多人肿瘤中的NQ 01活性比邻近正常组织中的NQ 01活性高50倍，表明p-lap可能在肿瘤中引起比正常组织更大的损伤。此外，电离辐射（IR）导致癌细胞中NQO 1活性的长期升高，因此，IR和p-lap协同作用杀死癌细胞。我们最近发现，在临床上可达到的温度下（例如<42 ℃）的高温也会导致癌细胞中NQO 1活性的长期升高，从而增强癌细胞对p-lap的反应。我们假设，已建立的肿瘤治疗方案，如放疗和热疗可以增强对肿瘤的p-lap细胞毒性，通过增加NQO 1在肿瘤细胞中的活性。本提案的总体目标是开发有效的方案，以通过利用放射疗法和热疗提高肿瘤中的NQO 1活性来选择性地增强肿瘤对p-lap的反应。具体目的是（1）确定IR对癌细胞的NQO 1水平和p-lap敏感性的影响，（2）确定单独的热疗或热疗与IR组合对癌细胞的NQO 1水平和p-lap敏感性的影响，（3）阐明P-lap单独或联合IR和热疗对体内肿瘤的反应;（4）阐明IR和热疗对P-lap作用的细胞和分子机制。和高血压诱导的NQO 1升高。