Improved Cryosurgical Destruction of Prostate Cancer

明确的目标。很明显，冷冻可以而且确实会摧毁前列腺癌和许多其他癌症的细胞和组织。冷冻外科用于治疗前列腺癌的使用正在增加，这一点从Campbell的泌尿学中包含了关于它的使用的一章中得到了证明，这是泌尿外科住院医师和从业者的标准文本[1]。基于我们最初的NIH R29支持的工作，我们已经证明，在啮齿动物和人类前列腺癌模型系统中，血管介导的损伤似乎主导着直接的细胞损伤[2-4](和初步结果)。然而，在临床上，一些接受冷冻手术的患者5年后会复发，这可能与最初的挑战有关，即治疗某些解剖区域附近的所有癌症，如直肠[5][6][7]。为了解决复发和控制的临床问题，以及进一步接受和应用这项技术，可以说需要更多的工作来重复定义并在可能的情况下扩大体内冷冻手术损伤的边缘。我们在裸鼠体内生长的人前列腺癌(LNCaP)的初步结果首次表明，通过使用适当的分子佐剂，可以摧毁冰球中冻结的所有组织。这一戏剧性的结果表明，我们确实有能力控制和延长体内的冷冻。定量描述导致这种破坏性增强的细胞和血管机制以及实现这一点的适当分子佐剂是本意见书的主题。以下假设和具体目标构成了研究这些问题的框架：假设。在血管内皮细胞水平上的直接细胞冷冻损伤以及随后的内皮细胞激活和血管炎症决定了体内冷冻的程度。 SA-1-建立体外培养的人内皮细胞(MVECs)和LNCaP的直接细胞损伤(DCL)条件，并评估分子佐剂的增强作用。 SA 2-在背部皮肤折叠室(DSFC)模型中建立体内冷冻损伤的温度阈值和细胞和分子性质。 使用分子佐剂(直接细胞和血管)建立和加强体内冷冻损伤的机制(S)。

SPECIFIC AIMS. It is clear that freezing can and does destroy the cells and tissues of prostate cancer as well as many other cancers. The use of cryosurgery to treat prostate cancer is growing as evidenced by the inclusion of a chapter on its use in Campbell's Urology, the standard text for urology residents and practitioners [1]. Based on our original NIH R29 supported work, we have demonstrated that vascular mediated injury appears to dominate direct cell injury within both a rodent and human prostate cancer model system [2-4] (and Preliminary Results). Nevertheless, clinically there is recurrence of the disease after 5 years in some cryosurgically treated patients which may be connected with the initial challenge of treating all of the cancer near certain anatomical areas such as the rectum [5] [6] [7]. In order to address the clinical issues of recurrence and control as well as further the acceptance and application of the technique, arguably more work is needed to reproducibly define and, if possible, extend the edge of the cryosurgical lesion in vivo. Our preliminary results in human prostate cancer (LNCaP) grown in a nude mouse show for the first time the capability of destroying all tissue frozen within an iceball by use of an appropriate molecular adjuvant. This dramatic result suggests that we may indeed be capable of both controlling and extending the cryolesion in vivo. Quantitative description of the cell and vascular mechanisms responsible for this destructive enhancement as well as the appropriate molecular adjuvants to achieve this are the topic of this submission. The following hypothesis and specific aims create a framework to study these issues: Hypothesis. Direct cell cryo-injury at the level of the vascular endothelium followed by endothelial cell activation and vascular inflammation determines the extent of the cryolesion in vivo. SA 1 - Establish Conditions for Direct Cell Injury (DCl) in human Endothelial Cells (MVECs) and LNCaP In Vitro and Assess Augmentation by Molecular Adjuvants. SA 2- Establish Thermal Thresholds and Cellular and Molecular Nature of In Vivo Cryo- Injury in a Dorsal Skin Fold Chamber (DSFC) Model. SA3- Establish and Enhance Mechanism(s) of In Vivo Cryoinjury Using Molecular Adjuvants (Direct Cell and Vascular) Within the DSFC System.