Radiation, Hormones & Antisense Prostate Cancer Therapy

描述(申请人提供)：简而言之，主要目的是(1)在一项针对前列腺癌合并中高危前列腺癌患者的III期随机试验中测试图像引导的低分割调强放射治疗(IMRT)的疗效；(2)建立在雄激素剥夺(AD)和非雄激素剥夺(AD)的情况下放射治疗(RT)后bcl2和bax的异常表达与患者预后的关系；(3)使用肿瘤模型确定基于减少bcl2表达的反义策略是否会改善前列腺癌对AD、RT和AD+RT的反应。放射治疗，单独或与AD合并，仍然是中到高风险患者的主要治疗方法。应用RT、整合AD+RT以及通过操纵细胞凋亡途径进一步促进细胞杀伤的最佳方法仍有待确定。这项工作的主要假设是：(1)使用IMRT在低分割方案中提供更高的生物剂量可以显著增强免于生化和/或疾病失败(FFF)的能力，(2)关键的凋亡途径蛋白bcl-2和bax的异常表达对放射反应产生不利影响，以及(3)bcl-2和bax控制前列腺癌对AD、RT和AD+RT的反应，从而通过反义bcl-2(AS-bCL-2)和/或反义cAMP依赖的蛋白激酶A型(AS-PKA)调节这些凋亡途径蛋白将使前列腺癌细胞对这些治疗更加敏感。这项临床试验在300名患者中比较了38次76次和26次70.2次(生物学上相当于84.3GY，假设α/β为1.5)的FFF和毒性。本试验和两个放射治疗肿瘤组试验(86-10和92-02)的前瞻性诊断组织将采用免疫组织化学方法检测bcl-2和bax，并与患者预后相关。用野生型、bcl2高表达和雄激素剥夺抗性LNCaP细胞研究AS-bcl2和AS-PKA改变bcl2表达对体外细胞死亡和体内原位肿瘤生长的影响。

DESCRIPTION (provided by applicant): The main aims, in brief, are to (1) test the efficacy of image-guided hypofractionated intensity modulated radiotherapy (IMRT) in a Phase III randomized trial of prostate cancer patients with intermediate-to-high risk prostate cancer, (2) establish the relationship of abnormal bcl-2 and bax expression to patient outcome after radiotherapy (RT) with and without androgen deprivation (AD), and (3) determine if antisense strategies based on reducing bcl-2 expression will improve prostate cancer response to AD, RT, and AD+RT using tumor models. Radiotherapy, given alone or in combination with AD, remains the mainstay of treatment for intermediate-to-high risk patients. The best methods for administering RT, integrating AD+RT, and further promoting cell killing via manipulation of the apoptotic pathway remain to be established. The primary hypotheses of the work proposed are that (1) freedom from biochemical and/or disease failure (FFF) may be significantly enhanced using IMRT to deliver higher biologic doses in a hypofractionated regimen, (2) the abnormal expression of the key apoptotic pathway proteins bcl-2 and bax adversely effect radiation response, and (3) bcl-2 and bax control prostate cancer response to AD, RT and AD+RT such that the modulation of these apoptotic pathway proteins via antisense bcl-2 (AS-bcl-2) and/or antisense cAMP-dependent protein kinase A type I (AS-PKA) will render prostate cancer cells more sensitive to these treatments. The clinical trial compares FFF and toxicity after 76 Gy in 38 fractions to 70.2 Gy in 26 fraction (biologically equivalent to 84.3 Gy assuming an alpha/beta of 1.5) in 300 patients. Bcl-2 and bax will be measured immunohistochemically in diagnostic tissue prospectively from this trial and retrospectively from two Radiation Therapy Oncology Group trials (86-10 and 92-02), and correlated with patient outcome. The effect of altering bcl-2 expression with AS-bcl-2 and AS-PKA on cell death in vitro and orthotopic tumor growth in vivo will be determined using wild type, bcl-2 overexpressing, and androgen deprivation resistant LNCaP cells.