Improved Cryosurgical Destruction of Prostate Cancer

具体的目标。很明显，冷冻可以而且确实会破坏前列腺癌的细胞和组织以及许多其他癌症。冷冻手术治疗前列腺癌的使用正在增长，这一点可以从坎贝尔泌尿外科的一章中得到证明，这是泌尿外科住院医生和从业人员的标准文本。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了直接细胞损伤[2-4]（和初步结果）。然而，在临床上，一些冷冻手术患者在5年后出现疾病复发，这可能与治疗某些解剖区域（如直肠b[6][6][7]）附近的所有癌症的初始挑战有关。为了解决复发和控制的临床问题，以及进一步接受和应用该技术，可以说需要做更多的工作来重复定义，如果可能的话，延长体内冷冻病变的边缘。我们在裸鼠中培养的人类前列腺癌（LNCaP）的初步结果首次表明，使用适当的分子佐剂可以破坏冰球内冷冻的所有组织。这一戏剧性的结果表明，我们可能确实有能力控制和延长体内冷冻创口。定量描述细胞和血管机制负责这种破坏性增强，以及适当的分子佐剂来实现这一目标是本次提交的主题。以下假设和具体目标为研究这些问题创建了一个框架：细胞在血管内皮水平的直接低温损伤，随后的内皮细胞活化和血管炎症决定了体内冻疮的程度。

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.