The long term objectives of this research proposal are to delineate cellular and molecular mechanisms of action involved in photodynamic therapy (PDT) and to evaluate methods for enhancing the efficacy of PDT. Clinical use of PDT continues to produce promising responses, and controlled Phase II and Phase III trials of PDT using Photofrin II (dihematoporphyrin-ether) have been initiated under the sponsorship of the Lederal Division of American Cyanamid. Enthusiasm for PDT continues to grow, but information related to basic in-vitro and in-vivo mechanisms associated with PDT needs to be obtained in order to fully evaluate the clinical potential of this modality. Cellular procedures will be utilized in isolating PDT resistant tumor cell strains. These cell strains will subsequently be used for molecular, biochemical and cellular characterization studies as well as for evaluating in-vivo PDT responses. A comprehensive evaluation of PDT sensitivity of cellular components of the vasculature will be performed utilizing cloned human and bovine cells. PDT Induces the over expression of oxidative stress proteins and this property will now be exploited in order to document in-vivo PDT target sites in treated tumors. In this regard, in-situ hybridization (using cDNA's to stress protein genes) will be performed in order to document the sites and kinetics of PDT induced oxidative stress protein mRNA expression. In-vivo procedures will also be utilized to study the adjunctive use of the hypoxic cell cytotoxin (SR-4233) with PDT. Quantitative tumor and normal tissue responses will be documented as a function of drug doses, light doses and time intervals between injections and treatments. New photosensitizers with photochemical and photobiological properties which appear to be superior to Photofrin II are available for basic research, and thereforee, both Photofrin II (the porphyrin undergoing current clinical evaluation) and new photosensitizers (such as chlorins and phthalocyanines) will be investigated in this proposal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA031230-08
Application #
3482207
Study Section
Radiation Study Section (RAD)
Project Start
1982-03-01
Project End
1994-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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Ferrario, A; Kessel, D; Gomer, C J (1992) Metabolic properties and photosensitizing responsiveness of mono-L-aspartyl chlorin e6 in a mouse tumor model. Cancer Res 52:2890-3

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