Photodynamic therapy (PDT)is a promising new modality for the treatment of cancer. In typical protocols, photosensitizers that localize preferentially within tumors are administered to individuals. Their activation by high intensity visible light results in tumor destruction. Investigation into the in vivo mechanisms by which PDT causes tumor destruction is essential if PDT protocols are to be optimized and if newer more effective photosensitizing agents are to be developed. Silicon phthalocyanine 4 (Pc4) is a promising new second generation photosensitizer that is being evaluated for the PDT. Studies by the applicant's group have shown that Pc 4 PDT-induced tumor regression can be diminished by neutralizing antibodies to the adhesion molecule ICAM-1 (CD54). ICAM-1 is a molecule that is critical for the development of immune and inflammatory reactions. They have also found the Pc 4PDT is immunosuppressive when given to mice. Based on these findings, the applicant hypothesizes that the immune and inflammatory processes initiated by Pc4 PDT play an important role in tumor regression and cure, and that manipulation of the immune and inflammatory response will significantly improve its ultimate efficacy. Initial studies will extend their observations regarding the role of ICAM-1 in Pc 4 PDT by determining whether its presence on the tumor or on the host is of greater importance for tumor regression. RIF-1 tumors, rendered deficient in ICAM-1 by antisense constructs will be used to evaluate the importance of tumor-derived ICAM-1. ICAM-1 deficient mice will be employed to assess the significance of ICAM-1 on the host. The role of the adhesion molecules E- and P-selectin, which are critical for migration of leukocytes into inflammatory sites will be examined for their participation in Pc 4 PDT-induced tumor regression. Immunohistochemistry and E-selectin, P-selectin and combined E- and P-selectin knockout mice will be used for this purpose. The applicant will define the types of inflammatory cells involved in Pc 4 PDT-induced tumor regression by phenotypic characterization of the leukocytes that infiltrate tumors before and after Pc 4 PDT. In vivo antibody depletion studies will then be performed to determine the effect of these cells on tumor regression. Finally, attempts will be made to identify mediators responsible for Pc 4 PDT-induced immunosuppression. Once they have been characterized, their activity will be neutralized during Pc 4 PDT tumor regression protocols in order to determine whether this procedure will increase tumor regression and/or improve tumor cures. The long-term goal of these studies is to generate new knowledge regarding the in vivo mechanisms by which PDT works so that it can be used more effectively to treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA086172-01
Application #
6130913
Study Section
Special Emphasis Panel (ZRG1-SSS-N (03))
Program Officer
Stone, Helen B
Project Start
2000-04-18
Project End
2005-03-31
Budget Start
2000-04-18
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$286,673
Indirect Cost
Name
University of Alabama Birmingham
Department
Dermatology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Pradhan, Sanjay; Kim, Hee Kyung; Thrash, Christopher J et al. (2008) A critical role for the proapoptotic protein bid in ultraviolet-induced immune suppression and cutaneous apoptosis. J Immunol 181:3077-88
Timares, Laura; Katiyar, Santosh K; Elmets, Craig A (2008) DNA damage, apoptosis and langerhans cells--Activators of UV-induced immune tolerance. Photochem Photobiol 84:422-36
Pradhan, Sanjay; Genebriera, Joseph; Denning, Warren L et al. (2006) CD4 T cell-induced, bid-dependent apoptosis of cutaneous dendritic cells regulates T cell expansion and immune responses. J Immunol 177:5956-67
Krishnan, Rajagopal; Pradhan, Sanjay; Timares, Laura et al. (2006) Fluorescence of sunscreens adsorbed to dielectric nanospheres: parallels to optical behavior on hacat cells and skin. Photochem Photobiol 82:1557-65
Huang, Chun-Ming; Elmets, Craig A; van Kampen, Kent R et al. (2005) Prospective highlights of functional skin proteomics. Mass Spectrom Rev 24:647-60
Huang, Chun-Ming; Elmets, Craig A; Tang, De-chu C et al. (2004) Proteomics reveals that proteins expressed during the early stage of Bacillus anthracis infection are potential targets for the development of vaccines and drugs. Genomics Proteomics Bioinformatics 2:143-51
Elmets, Craig A; Yusuf, Nabiha; Hamza, Sate et al. (2004) Topical application of dimethylbenz[a]anthracene results in the generation of multiple melanocytic nevi in C3H/HeN mice. Toxicol Appl Pharmacol 195:355-60
Katiyar, S K; Bergamo, B M; Vyalil, P K et al. (2001) Green tea polyphenols: DNA photodamage and photoimmunology. J Photochem Photobiol B 65:109-14