Radiation, Hormones & Antisense Prostate Cancer Therapy

描述（由申请人提供）：简而言之，主要目的是(1)在一项针对中高风险前列腺癌患者的III期随机试验中测试图像引导下低分割强度调节放疗（IMRT）的疗效，(2)建立伴有和不伴有雄激素剥夺（AD）的前列腺癌患者放疗（RT）后bcl-2和bax异常表达与预后的关系。(3)通过肿瘤模型确定基于降低bcl-2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。放疗，单独给予或与AD联合给予，仍然是中高危险患者的主要治疗方法。给予RT、整合AD+RT以及通过操纵凋亡通路进一步促进细胞杀伤的最佳方法仍有待建立。这项工作提出的主要假设是：(1)通过低分离方案的高生物剂量的IMRT可以显著增强生化和/或疾病失败（FFF）的自由度，(2)关键凋亡途径蛋白bcl-2和bax的异常表达会对辐射反应产生不利影响，(3)bcl-2和bax控制前列腺癌对AD的反应。通过反义bcl-2 （AS-bcl-2）和/或反义camp依赖性蛋白激酶A型I （AS-PKA）调节这些凋亡通路蛋白，使前列腺癌细胞对这些治疗更敏感。该临床试验比较了300名患者中76 Gy（38份）和70.2 Gy（26份）的FFF和毒性（生物学上相当于84.3 Gy，假设α / β为1.5）。本试验和两项放射治疗肿瘤学组试验（86-10和92-02）将对诊断组织中的Bcl-2和bax进行前瞻性免疫组织化学测定，并与患者预后相关。用AS-bcl-2和AS-PKA改变bcl-2表达对体外细胞死亡和体内原位肿瘤生长的影响将通过野生型、bcl-2过表达和抗雄激素剥夺的LNCaP细胞来确定。

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.