Tumor necrosis factor-alpha-induced accentuation in cryoinjury: mechanisms in vitro and in vivo.

Abstract

Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-alpha (TNF-alpha) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5 degrees C) over the current clinical recommendation of reaching temperatures lower than -40 degrees C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-alpha-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-alpha. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-alpha doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-kappaB-mediated inflammatory or caspase-mediated apoptosis pathways. The amount of cryoinjury increased in a dose-dependent manner with TNF-alpha both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-alpha. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-alpha doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-kappaB-mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelial-mediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-alpha to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball.

• Authors: Jing Jiang, Raghav Goel, M Arif Iftekhar, Rachana Visaria, John D Belcher, Gregory M Vercellotti, John C Bischof
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 8 Pg. 2547-55 (Aug 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18723499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Recombinant Proteins
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Cryosurgery
• Humans
• In Vitro Techniques
• Male
• Mice
• NF-kappa B (antagonists & inhibitors)
• Recombinant Proteins (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)