Merocyanine 540 (MC540) is a membrane-directed photosensitizing dye which can function as a highly selective antitumor and antiviral agent. Oncologic interest in MC540 is based on its ability to mediate the photoinactivation of neoplastic cells (leukemia, lymphoma, or neuroblastoma cells) in autologous remission bone marrow grafts. Elimination of tumor cells in this fashion is an exciting prospect for improving the success rate of """"""""rescue"""""""" engraftment in leukemia patients undergoing intensive chemotherapy or radiation therapy after a relapse. Pathogenic enveloped viruses can also be selectively inactivated by MC540/light treatment, suggesting a new strategy for sterilizing virus- infected bone marrow, blood, or blood products. The three projects and one core that comprise this program are linked by a common goal of achieving a better understanding of MC540 photosensitization from the physico-chemical, biochemical, and biomedical perspective. The joint program is the first to explore this area in comprehensive, interdisciplinary fashion and has made considerable progress during the existing grant period. Two new aspects are introduced in the continuing work: (i) Synthesis and evaluation of several new MC540 analogs, both non-labeled and radiolabeled; and (ii) In-depth studies on MC-mediated photoinactivation of viruses, e.g. herpes simplex virus type 1 (HSV-1). Some key objectives are as follows. Project I: Study photochemical/photophysical properties of MC540 analogs in model membranes and leukemia cells; examine salicylate as a mechanistic probe and also potentiator of MC/light-induced cell killing; characterize MC photoproducts exhibiting antileukemic and antiviral properties. Project II: Examine MC-sensitized lipid damage (peroxidation) and protein damage (e.g. cross-linking, Ca2+ leaks) in relation to one another and also cell killing; study role of iron in MC-mediated phototoxicity; study selenium/glutathione-dependent cytoprotection against photodamage and photokilling. Project III: Screen MC540 analogs for antileukemic and antiviral properties; test biological activity of dye photoproducts; perform comparative cell binding and pharmacokinetic studies on MC dyes; collaborate in clinical trial involving MC540/light-mediated bone marrow purging. Techniques to be used include electron spin resonance, gas chromatography, mass spectrometry, high performance liquid chromatography, fluorescence polarization; flow cytometry, and clonal assay. The proposed work will provide a strong foundation upon which to base rational clinical applications of MC/light treatment for the eradication of neoplastic cells and pathogenic viruses.
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