TRIMODAL GENE THERAPY FOR PROSTATE CANCER

说明(改编自应用程序) 前列腺癌是男性最常见的恶性肿瘤。虽然 传统的治疗方法(手术、放射治疗、雄激素消融)会产生很高的 早期疾病治愈率高，肿瘤复发多，疗效显著 对于这种疾病的晚期，仍然缺乏治疗方案。我们的 研究计划开发了一种新的、多方面的基因治疗方法 前列腺癌的治疗。我们的方法利用修改后的复制 强力腺病毒(FGR)选择性高效地递送一对 治疗前列腺癌的自杀基因。动物的临床前研究 已经证明FGR病毒本身产生了一种强大的抗肿瘤作用 通过复制并优先摧毁人前列腺癌细胞 缺乏功能性的P53肿瘤抑制蛋白。丹参的临床疗效观察 FGR病毒可以通过调用两个自杀基因系统(CD/5FC和CD/5FC)来增强 HSV1 TK/GCV)，使恶性细胞对特定的 药理剂(前药物)，更重要的是，使他们对 辐射。我们方法的一个优点是它同时利用了 三种方式的病毒，双自杀基因和放射治疗 选择性地摧毁前列腺癌细胞，毒性最小，接近正常 纸巾。 我们的研究工作目前正处于临床前/I期临床的尖端 学习。涉及FGR病毒的I期临床方案 我们的IRB已经批准了双前药疗法。与IND前的会议 FDA已经举行了会议，我们预计将在1999年开始I期试验。作为一种手段 进一步提高我们的方法的有效性，这一应用将：1) 评估雄激素消融术作为第四个治疗臂的优点，2) 评价FGR病毒治疗播散性疾病的效果， 3)评价各治疗臂对肿瘤的特异性 并确定治疗失败是否与P53状态相关。

DESCRIPTION (adapted from application) Prostate cancer is the most commonly diagnosed malignancy in men. Although conventional therapies (surgery, radiation, androgen ablation) produce high cure rates of early stage disease, many tumors recur and an effective therapeutic regimen is still lacking for advanced stages of the disease. Our research program has developed a novel, multifaceted, gene therapy approach for the treatment of prostate cancer. Our approach utilizes a modified, replication competent adenovirus (FGR) to selectively and efficiently deliver a pair of therapeutic suicide genes to prostate tumors. Preclinical studies in animals have demonstrated that the FGR virus itself generates a potent antitumor effect by replicating in and preferentially destroying human prostate cancer cells that lack a functional p53 tumor suppressor protein. The therapeutic effect of the FGR virus can be enhanced by invoking two suicide gene systems (CD/5FC and HSV1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents (prodrugs), and more importantly, sensitizes them to radiation. A strength of our approach is that it simultaneously makes use of three modalities viral, double suicide gene, and radiation therapies to selectively destroy prostate cancer cells with minimal toxicity towards normal tissues. Our research efforts are currently at the cusp of preclinical/phase I clinical studies. A phase I clinical protocol involving the FGR virus concomitant with double prodrug therapy has been approved by our IRB. A pre-IND meeting with the FDA has been held, and we expect to begin phase I trials in 1999. As a means to further enhance the efficacy of our approach, this application will: 1) evaluate the merit of adding androgen ablation as a fourth therapeutic arm, 2) evaluate the effectiveness of FGR viral therapy against disseminated disease, and 3) evaluate the specificity of each therapeutic arm with respect to tumor p53 status and determine whether treatment failure correlates with p53 status.