Evidence is provided that Photodynamic Therapy (PDT) can affect vascular permeability to macromolecules and macromolecular complexes in a way that allows enhanced tumor uptake of therapeutic agents in human tumor xenografts or in transplantable murine tumors. This can lead to significantly enhanced tumor control, as shown with liposome-encapsulated doxorubicin. The PDT protocol, termed """"""""permeabilizing"""""""" (P)-PDT, differs from conventional PDT in that it by itself has no or minimal anti-tumor effects. At present, this protocol involves the interaction of two photosensitizers, an anionic pyropheophorbide derivative (HPPH) and the cationic dye Victoria Blue-BO (VBBO). Understanding and exploiting the mechanisms by which P-PDT lowers the vascular barrier encountered by large molecular therapeutic agents may provide an additional approach in the treatment of solid tumors. The preliminary data have led to the hypothesis that P-PDT affects the microvasculature by opening endothelial gaps that allow macromolecules to egress from the vasculature and enter the interstitial tumor space. The applicant further hypothesizes that this mechanism will facilitate the egress of liposomes and microspheres carrying chemotherapeutic drugs or immunomodulating cytokines, thus enhancing cytotoxicity or stimulating anti-tumor immune responses, or of viral gene vectors enhancing transfection efficiencies. The overall goal of this application is to conduct a series of experiments that will test these possibilities.
In Aim 1 the applicant proposes to optimize treatment parameters by exploring additional treatment regimes and photosensitizers. These experiments will not only improve the treatment, but also provide important hints as to the mechanisms involved.
In Aim 2 she proposes to expand the application of this treatment from the delivery of liposomally carried chemotherapeutic drugs to microspheres carrying the cytokine GM-CSF and a viral gene vector expressing the beta-galactosidase (beta-gal) gene.
Aim 3 will focus on the mechanisms of macromolecular egress by determining the size of vascular gaps produced, by monitoring changes in perfusion and permeability in real time by functional MRI, and by administering a number of inhibitors to physiological vasoactive mediators Finally, in Aim 4 she proposes to add a therapeutic PDT component by activating the present photosensitizers with therapeutic light doses that cause photodynamic tumor destruction. She hypothesizes that this added cytoreduction by PDT after maximal chemotherapeutic drug uptake will be beneficial for tumor control. Similarly, PDT destroyed tumor cells may provide tumor antigen to differentiating dendritic cells generated by preceding delivery of GM-CSF.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042278-15
Application #
6512371
Study Section
Special Emphasis Panel (ZRG1-SSS-N (03))
Program Officer
Stone, Helen B
Project Start
1986-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
15
Fiscal Year
2002
Total Cost
$329,815
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Seshadri, Mukund; Bellnier, David A; Vaughan, Lurine A et al. (2008) Light delivery over extended time periods enhances the effectiveness of photodynamic therapy. Clin Cancer Res 14:2796-805
Henderson, Barbara W; Busch, Theresa M; Snyder, John W (2006) Fluence rate as a modulator of PDT mechanisms. Lasers Surg Med 38:489-93
Snyder, John W; Greco, William R; Bellnier, David A et al. (2003) Photodynamic therapy: a means to enhanced drug delivery to tumors. Cancer Res 63:8126-31
Henderson, B W; Busch, T M; Vaughan, L A et al. (2000) Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate. Cancer Res 60:525-9
Henderson, B W; Sitnik-Busch, T M; Vaughan, L A (1999) Potentiation of photodynamic therapy antitumor activity in mice by nitric oxide synthase inhibition is fluence rate dependent. Photochem Photobiol 70:64-71
Sitnik, T M; Henderson, B W (1998) The effect of fluence rate on tumor and normal tissue responses to photodynamic therapy. Photochem Photobiol 67:462-6
Sitnik, T M; Hampton, J A; Henderson, B W (1998) Reduction of tumour oxygenation during and after photodynamic therapy in vivo: effects of fluence rate. Br J Cancer 77:1386-94
Henderson, B W; Vaughan, L; Bellnier, D A et al. (1995) Photosensitization of murine tumor, vasculature and skin by 5-aminolevulinic acid-induced porphyrin. Photochem Photobiol 62:780-9
Bellnier, D A; Henderson, B W; Pandey, R K et al. (1993) Murine pharmacokinetics and antitumor efficacy of the photodynamic sensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a. J Photochem Photobiol B 20:55-61
Mayhew, E; Vaughan, L; Panus, A et al. (1993) Lipid-associated methylpheophorbide-a (hexyl-ether) as a photodynamic agent in tumor-bearing mice. Photochem Photobiol 58:845-51

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