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：
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
项目类别：
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

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-2H-萘酚[1,2-B] pyran-5,6-二酮）是一种实验性抗 - 最初从拉帕乔树获得的癌药物。 p圈会导致各种人类癌细胞中的细胞死亡。 I和II期临床试验，以研究单独使用或与其他化学疗法药物结合使用的3圈的安全性和有效性。这些临床试验基于以下假设：P-LAP通过激活细胞周期检查点杀死癌细胞。另一方面，我们的假设是，通过NAD（P）H：喹酮氧化还原酶（NQ01）的介导P-LAP的生物激活会导致细胞中的分子变化导致细胞死亡。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活性是相邻正常组织的50倍，表明p-lap相对于正常组织，肿瘤可能造成更大的损害。此外，电离辐射（IR）导致癌细胞中NQO1活性的持久升高，因此IR和P-LAP在杀死癌细胞中有效地反应。我们最近发现，在临床上可达到的温度下，高温，例如<42oC，还会引起癌细胞中NQO1活性的长期升高，从而增强了癌细胞对P-LAP的反应。我们假设建立的肿瘤治疗方案（例如放疗和高温治疗）可以通过增加肿瘤细胞中NQO1活性来增强肿瘤的p闭合细胞毒性。本提案的总体目的是开发有效的方案，通过升高利用放射疗法和高温的肿瘤中的NQO1活性来选择性增强肿瘤对P-lap的反应。具体目的是（1）确定IR对癌细胞NQO1水平和p-lap敏感性的影响，（2）单独或与IR与IR合并对NQ01水平的影响和癌细胞的P-LAP敏感性的影响，（3）阐明体内肿瘤对IR和高温和组合的肿瘤对P-LAP的反应，以及（4）划定IR-和高温诱导的NQO1升高的细胞和分子机制。