Department of Cell Stress Biology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo New York USA 14263
Tel: 716-845-7679
Fax: 716-845-8920
E-mail: David.Bellnier@Roswellpark.org

Description of Research

Photodynamic Therapy: Basic and Translational Research
The objective of this program is to devise and implement more effective approaches to Photodynamic Therapy (PDT). PDT involves the administration of a photodynamically-active drug (photosensitizer) or pro-drug followed by drug-activating visible light. This therapy has been successfully applied to both neoplastic and non-neoplastic diseases.

This research program takes place in the multidisciplinary, highly interactive environments of the Photodynamic Therapy Center and the Biophysical Therapies Program. As such, numerous lines of attack are being taken to improve both the efficacy and selectivity of PDT, including (i) the rational design, synthesis and testing of new photosensitizers ^{1, 2} [directed by Dr. Pandey in our group], (ii) the design and application of optimal therapeutic regimens, e.g., drug dosage and schedule based on phamacokinetic/pharmacodynamic studies³ [directed by Dr. Bellnier] and light dosage and schedule based on fluence/fluence rate studies⁴ [directed by Dr. Henderson in our group] and (iii) the study of multimodal approaches ^5-7.

We are currently studying the interaction of the antivascular agent DMXAA (5,6-dimethylxanthenone-4-acetic acid) with PDT ⁴. Although DMXAA does not appear to be directly cytotoxic to tumor cells, it induces biological responses that include early-onset endothelial cell apoptosis, the production of cytokines by both host and tumor cells, as well as the induction of vasoactive compounds like NO and serotonin. The synthesis of the cytokine TNF-alpha is largely responsible for DMXAA’s dramatic antitumor-antivascular effects in murine tumors and xenografts. We have shown that neoadjuvant DMXAA dramatically increases the antitumor activity of Photofrin-sensitized PDT in rodent tumor models, and have observed a similar interaction between DMXAA and delta-aminolevulinic acid (ALA)-protoporphyrin IX-sensitized PDT. Recent experiments, in conjunction with Dr. Gollnick, suggest that DMXAA may initiate an antitumor immune response. Studies of DMXAA and PDT based on HPPH, a second generation photosensitizer in RPCI-sponsored clinical trials, are underway.

Selected Publications

1. Henderson BW, DA Bellnier, WR Greco, A Sharma, RK Pandey, LA Vaughan, KR Weishaupt and TJ Dougherty. An in vivo quantitative structure-activity relationship for a congeneric series of pyropheophorbide derivatives as photosensitizers for photodynamic therapy. Cancer Res 57:4000-4007, 1997.
2. Zheng G, WR Potter, SH Camacho, JR Missert, G Wang, DA Bellnier, BW Henderson, MAJ Rodgers, TJ Dougherty and RK Pandey. Synthesis, photophysical properties, tumor uptake, and preliminary in vivo photosensitizing efficacy of a homologous series of 3-(1¢-alkyoxy)ethyl-3-devinylpurpurin-18-N-alkylimides with variable lipophilicity. J Med Chem 44:1540-1559, 2001.
3. Bellnier DA, WR Greco, H Nava, AR Oseroff, GM Loewen, T Tsuchida, RK Pandey and TJ Dougherty. Population pharmacokinetics of the photodynamic therapy agent 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in cancer patients. Cancer Res 63:1806-1813, 2003.
4. Henderson BW, TM Busch, LA Vaughan, NP Frawley, D Babich, TA Sosa, JD Zollo, AS Dee, MT Cooper, DA Bellnier, WR Greco and AR Oseroff. Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate. Cancer Res 60:525-529, 2000.
5. Snyder JW, WR Greco, DA Bellnier, L Vaughan and BW Henderson. Photodynamic therapy: A means to enhanced drug delivery to tumors. Cancer Res 63:8126-8131, 2003.
6. Bellnier DB, SO Gollnick, SH Camacho, WR Greco and RT Cheney. Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxantheone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 tumors. Cancer Res 63:7584-7590, 2003.
7. Bellnier DA. Potentiation of photodynamic therapy in mice with recombinant human tumor necrosis factor-alpha. J Photochem Photobiol 8:203-210, 1991.