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

基本信息

批准号：
7335560
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
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7335560
关键词：
1-naphthol Antineoplastic Agents Apoptosis Back Biological Factors Calpain Cell Cycle Checkpoint Cell Death Cells Clinical Trials Effectiveness Electrons Elevation Endopeptidases 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 Mitomycin Molecular Mus NAD(P)H dehydrogenase (quinone) 1, human NADH NQO1 gene Naphthols Normal tissue morphology Oxidoreductase Peptide Hydrolases Pharmaceutical Preparations Phase Purpose Pyrans Quinones Radiation Radiation Tolerance Radiation therapy Relative (related person)Reporting Role Safety Source South America T-Lymphocyte Temperature Time Toxic effect Transcriptional Activation Treatment Protocols Trees Up-Regulation base benzoquinone cancer cell cancer therapy cell killing chemotherapy cytochrome c cytotoxicity hydroquinone hyperthermia treatment in vivo irradiation killings neoplastic cell repaired response tumor

项目摘要

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）：p-Lapachone(p-Lap)(3,4-二氢-2,2-二甲基-2H-萘酚[1,2-b]吡喃-5,6-二酮)是一种实验性抗-最初从拉帕乔树中获得的抗癌药物。 P-Lap 会导致多种人类癌细胞死亡。其他地方正在进行研究 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的 I 期和 II 期临床试验。这些临床试验基于这样的假设：p-lap 通过激活细胞周期检查点来杀死癌细胞。另一方面，我们的假设是，p-lap 通过 NAD(P)H:醌氧化还原酶 (NQ01) 的介导进行生物激活，诱导细胞内分子级联变化，导致细胞死亡。因此，p-lap的细胞毒性与细胞NQO1水平的活性密切相关。重要的是，许多人类肿瘤中的 NQ01 活性比邻近正常组织高出 50 倍，这表明 p-lap 可能对肿瘤造成比正常组织更大的损害。此外，电离辐射 (IR) 会导致癌细胞中 NQO1 活性长期持续升高，因此 IR 和 p-lap 协同反应杀死癌细胞。我们最近发现，在临床可达到的温度下进行热疗，例如<42oC，还会导致癌细胞中 NQO1 活性长期持续升高，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（例如放疗和热疗）可以通过增加肿瘤细胞中的 NQO1 活性来增强 p-lap 对肿瘤的细胞毒性。本提案的总体目标是开发有效的方案，通过利用放疗和热疗提高肿瘤中的 NQO1 活性来选择性增强肿瘤对 p-lap 的反应。具体目标是 (1) 确定 IR 对癌细胞 NQO1 水平和 p-lap 敏感性的影响，(2) 确定单独热疗或与 IR 结合使用对癌细胞 NQ01 水平和 p-lap 敏感性的影响，（3）阐明体内肿瘤对单独和组合IR和热疗的P-lap的反应，（4）描述IR和热疗诱导NQO1升高的细胞和分子机制。