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

描述(申请人提供)：p-Lapachone(p-Lap)(3，4-dihydro-2，2-dimethyl-2H-naphthol[1，2-b]pyran-5，6-dione)是一种实验性抗癌药物，最初从拉帕乔树中获得。P-LAP可导致多种人类癌细胞死亡。一期和二期临床试验正在其他地方进行，以调查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。这些临床试验是基于这样一种假设，即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，通过NAD(P)H：Quone氧化还原酶(NQ01)介导的p-LAP的生物激活导致细胞分子变化的级联反应，从而导致细胞死亡。因此，p-LAP的细胞毒性与细胞内NQO1活性水平密切相关。重要的是，在许多人类肿瘤中，NQ01的活性比邻近正常组织中的NQ01活性高50倍，这表明相对于正常组织，p-LAP可能对肿瘤造成更大的损害。此外，电离辐射(IR)导致癌细胞中NQO1活性的长期升高，因此，IR和p-LAP在杀灭癌细胞方面起协同作用。我们最近发现，在临床可达到的温度下，例如42摄氏度的高温，也会导致癌细胞中NQO1活性的长期升高，从而增强癌细胞对p-LAP的反应。我们假设，现有的肿瘤治疗方案，如放疗和热疗，可以通过增加肿瘤细胞中NQO1的活性来增强p-LAP对肿瘤的细胞毒作用。本提案的总体目标是开发有效的方案，通过提高肿瘤中NQO1的活性来选择性地增强肿瘤对p-LAP的反应，方法是利用放射治疗和热疗。其具体目标是(1)确定IR对癌细胞NQO1水平和P-LAP敏感性的影响，(2)确定单独或联合热疗对癌细胞NQ01水平和P-LAP敏感性的影响，(3)阐明体内肿瘤对IR和热疗单独或联合应用的反应，以及(4)阐明IR和热疗诱导NQO1升高的细胞和分子机制。

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.