Improved Cryosurgical Destruction of Prostate Cancer

具体目标。很明显，冷冻可以而且确实会破坏前列腺癌以及许多其他癌症的细胞和组织。冷冻手术治疗前列腺癌的使用正在增长，坎贝尔的《泌尿学》中包含了一章关于冷冻手术的使用，这是泌尿学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，我们已经证明血管介导的损伤似乎在啮齿动物和人前列腺癌模型系统中主导直接细胞损伤[2-4]（和初步结果）。然而，在临床上，在一些冷冻手术治疗的患者中，5年后疾病复发，这可能与治疗某些解剖区域（如直肠）附近的所有癌症的初始挑战有关[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的技术，可以说需要更多的工作，以可重复地定义，如果可能的话，延长体内冷冻损伤的边缘。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，能够破坏冷冻在冰球内的所有组织。这一引人注目的结果表明，我们可能确实能够在体内控制和延长冷冻损伤。定量描述的细胞和血管机制，负责这种破坏性的增强，以及适当的分子佐剂，以实现这一目标是本提交的主题。以下假设和具体目标创建了一个框架来研究这些问题：假设。血管内皮水平的直接细胞冷冻损伤，随后是内皮细胞活化和血管炎症，决定了体内冷冻损伤的程度。 SA 1 -在体外建立人内皮细胞（MVEC）和LNCaP中的直接细胞损伤（DCl）的条件并评估分子佐剂的增强作用。 SA 2-在背侧皮肤褶皱室（DSFC）模型中建立体内冷冻损伤的热稳定性和细胞及分子性质。 SA 3-在DSFC系统内使用分子佐剂（直接细胞和血管）建立和增强体内冷冻损伤机制。

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.