Pre-existing inflammation induced by TNF-alpha augments cryosurgery on human prostate cancer

Vascular injury is a major mechanism of cryosurgical destruction. The extent of vascular injury may be affected by the addition of molecular adjuvants. This study, in addition to determining the injury mechanism in the LNCaP Pro 5 human prostate cancer line grown in a nude mouse, examines the effect of cytokine TNF-α on cryosurgery of an in vivo microvascular preparation (Dorsal Skin Flap Chamber). Cryosurgery was performed in the chamber on either normal skin or tumor tissue. The area of vascular injury observed with FITC-labeled dextran quantitatively corresponded to the area of necrosis observed in histologic section after 3 days (p>0.5). There was complete destruction of the vasculature in the center of the lesion followed by an abrupt change to normal patency moving radially outward. A comparison of injury data to a thermal model indicated that the minimum temperature required for causing necrosis was 3.5±6.9°C in TNF-α-treated LNCaP Pro 5 tumor tissue (n = 4) and -9.8±5.8°C in TNF-α-treated normal skin of the nude mouse (n = 4). Comparing to tissues without TNF-α treatment, where the minimum temperature required for causing necrosis was -16.5±4.3°C in LNCaP Pro 5 human prostate tumor tissue (n = 8) and -24.4±7.0°C in normal skin of the nude mouse (n = 9), comparable to those found in the Copenhagen rat (p>0.05), the results indicated the local use of TNF-α would dramatically increase the thermal threshold of cryo-destruction by more than 10°C (p<0.01). In addition, the size of lesion from cryosurgery was larger in tumor tissue than that in normal skin after the same thermal history, either with or without TNF-α treatment (p<0.05). These findings are consistent with the hypothesis that vascular-mediated injury is responsible for defining the edge of the cryolesion in microvascular-perfused tissue, and therefore induced inflammation would augment cryoinjury. The local use of TNFα to pre-inflame prostate cancer promises to increase both the ability of freezing to destroy cancer as well as improving the ability of ultrasound or other iceball-monitoring techniques to predict the outcome of the treatment.