There is considerable interest for photodynamic therapy (PDT) as a new treatment modality in cancer patients. PDT consists of systemic administration of photosensitizing drugs, e.g., hematoporphyrin derivative (Hpd) or Photofrin II (enriched in hydrophobic porphyrins in Hpd), allowing them to accumulate in tumors, and exposing lesions to photoradiation (laser irradiation at 630 nm). Encouraging clinical results are seen in breast, lung, bladder, and head and neck tumors; controlled (protocol) studies are underway for bladder and lung cancers. Nevertheless, much research remains to elucidate the mechanisms producing tumor regression. There is a need to define the sites and events leading to cytotoxicity, the porphyrin species causing photosensitization, and identify and refine factors that can impact on optimization of therapeutic response. We are studying two well-differentiated rodent mammary tumor models, which we characterized extensively in vivo and in vitro. In previous studies, we developed an in vivo-in vitro protocol, using biochemical parameters as indicators of photosensitization, to assess sites of action; in this model, endogenous metabolism and its effect on pharmacokinetics occur, providing an opportunity to extend findings from studies in vitro. We now have considerable support for our thesis tht mitochondria are a critical site of action, with impaired ATP production leading to cellular demise. We propose to expand and extend these interesting findings to gain insight on factors enhancing target organ photosensitivity. Experiments are proposed to: 1) ascertain the sites of action and photosensitizing properties of Photofrin II in the functional in vivo-in vitro assay and study ATP levels in situ by NMR spectroscopy; 2) further define mitochondrial sites of action relative to mitochondrial topography; 3) evaluate in depth the role of oxygen as a factor for photosensitization, its effect on '02 production and resulting damage; 4) alter membrane lipid composition by dietary means as one way to enhance photosensitization; 5) assess photosensitivity as influenced by hormonal perturbations that affect tumor growth, e.g., estrogens, ovariectomy, etc., and metabolism such as thyroxine; and 6) initiate studies of selected perturbations for additivity of enhancing photosensitization. Results should provide new insight regarding mechanisms of actions leading to cytotoxicity and could lead to development of combined maneuvers to improve the efficacy of PDT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036856-08
Application #
3174430
Study Section
Radiation Study Section (RAD)
Project Start
1984-03-15
Project End
1992-06-30
Budget Start
1991-03-01
Budget End
1992-06-30
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
You, Youngjae; Gibson, Scott L; Hilf, Russell et al. (2003) Water soluble, core-modified porphyrins. 3. Synthesis, photophysical properties, and in vitro studies of photosensitization, uptake, and localization with carboxylic acid-substituted derivatives. J Med Chem 46:3734-47
Brennan, Nancy K; Hall, Jonathan P; Davies, Sherry R et al. (2002) In vitro photodynamic properties of chalcogenopyrylium analogues of the thiopyrylium antitumor agent AA1. J Med Chem 45:5123-35
Gibson, S L; Havens, J J; Metz, L et al. (2001) Is delta-aminolevulinic acid dehydratase rate limiting in heme biosynthesis following exposure of cells to delta-aminolevulinic acid? Photochem Photobiol 73:312-7
Bigelow, C E; Mitra, S; Knuechel, R et al. (2001) ALA- and ALA-hexylester-induced protoporphyrin IX fluorescence and distribution in multicell tumour spheroids. Br J Cancer 85:727-34
Finlay, J C; Conover, D L; Hull, E L et al. (2001) Porphyrin bleaching and PDT-induced spectral changes are irradiance dependent in ALA-sensitized normal rat skin in vivo. Photochem Photobiol 73:54-63
Stilts, C E; Nelen, M I; Hilmey, D G et al. (2000) Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy. J Med Chem 43:2403-10
Mitra, S; Foster, T H (2000) Photochemical oxygen consumption sensitized by a porphyrin phosphorescent probe in two model systems. Biophys J 78:2597-605
Hilf, R; Havens, J J; Gibson, S L (1999) Effect of delta-aminolevulinic acid on protoporphyrin IX accumulation in tumor cells transfected with plasmids containing porphobilinogen deaminase DNA. Photochem Photobiol 70:334-40
Hull, E L; Conover, D L; Foster, T H (1999) Carbogen-induced changes in rat mammary tumour oxygenation reported by near infrared spectroscopy. Br J Cancer 79:1709-16
Pearce, D A; Ferea, T; Nosel, S A et al. (1999) Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Nat Genet 22:55-8

Showing the most recent 10 out of 50 publications