The long term objective of this project is the development of Photodynamic Therapy (PDT) for application in the clinical management of patients with cancer. This goal will be accomplished by (1) gaining a more complete understanding of the basic mechanisms of PDT, and (2) conducting careful clinical studies in order to demonstrate safety and efficacy.
The specific aims of the basic science studies are to investigate the fundamental mechanism(s) of PDT action on tumor microvasculature at two levels: (1) Human dermal microvascular endothelial cells (MEC); and (2) tumor-induced capillary proliferation in the rabbit cornea.
The specific aims of the clinical studies are to determine the efficacy of PDT in Carcinoma In Situ (CIN) in the female genital tract employing topical (non-systemic) drug application. To elucidate further the mechanism(s) of PDT action on human MEC different photosensitizers will be studied with respect to: (1) cellular uptake/retention kinetics (2) subcellular localization/binding (3) subcellular phototoxicity (4) photosensitizer photobleaching and predictive value of fluorescence for phototoxicity (5) mechanism(s) of cellular uptake. Those photosensitizers that show significantly more PDT activity than PHOTOFRIN/R """"""""standard"""""""" in the human MEC culture studies will be evaluated in the rabbit cornea model. The purpose of these studies will be to elucidate the mechanism(s) of PDT action on tumor microvasculature by examining each of the photosensitizers with respect to: (1) light and drug dosimetry parameters for optimal tumor microvasculature destruction (2) light and electron microscopic study of the time course of tumor microvasculature destruction and (3) determination of photosensitizer localization in tumor microvasculature structures using electron microscope autoradiography. Once potential photosensitizers have demonstrated photosensitizing capabilities in cell culture experiments, a determination will be made in the rabbit cornea model of the relevant light and drug dosimetry parameters necessary to produce optimal tumor microvasculature destruction. The parameters to be studied are: (1) time interval between intravenous injection of photosensitizer and light exposure (2) photosensitizer (mg/kg body weight) and total light (J/cm2) doses (3) laser irradiation: power density (mW/cm2) and spot diameter. In order to study topical drug PDT (as opposed to systemic drug injection) in a human clinical setting, a randomized, placebo controlled study in 120-140 patients with CIN II or III of the cervix will be undertaken. Eligible patients will undergo colposcopy, cytology, and photographic documentation, and colposcopic guided biopsy of abnormal lesions. One month later, a repeat colposcopy, cytology and photographic documentation will be done to assure that spontaneous regression has not occurred and patients will then be randomized to PDT or control. Response will be evaluated at 3 month intervals for up to one year post treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032248-16
Application #
6150002
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1982-05-01
Project End
2003-01-31
Budget Start
2000-02-22
Budget End
2001-01-31
Support Year
16
Fiscal Year
2000
Total Cost
$341,758
Indirect Cost
Name
University of California Irvine
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Degen, Andrea F; Gabrecht, Tanja; Mosimann, Laurent et al. (2004) Photodynamic endometrial ablation for the treatment of dysfunctional uterine bleeding: a preliminary report. Lasers Surg Med 34:1-4
Kimel, Sol; Svaasand, Lars O; Hammer-Wilson, Marie J et al. (2003) Influence of wavelength on response to laser photothermolysis of blood vessels: implications for port wine stain laser therapy. Lasers Surg Med 33:288-95
Keefe, Kristin A; Tadir, Yona; Tromberg, Bruce et al. (2002) Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid. Lasers Surg Med 31:289-93
Hammer-Wilson, Marie J; Cao, Danielle; Kimel, Sol et al. (2002) Photodynamic parameters in the chick chorioallantoic membrane (CAM) bioassay for photosensitizers administered intraperitoneally (IP) into the chick embryo. Photochem Photobiol Sci 1:721-8
Chan, John K; Monk, Bradley J; Cuccia, David et al. (2002) Laparoscopic photodynamic diagnosis of ovarian cancer using 5-aminolevulinic acid in a rat model. Gynecol Oncol 87:64-70
Kimel, Sol; Svaasand, Lars O; Cao, Danielle et al. (2002) Vascular response to laser photothermolysis as a function of pulse duration, vessel type, and diameter: implications for port wine stain laser therapy. Lasers Surg Med 30:160-9
Keefe, K A; Chahine, E B; DiSaia, P J et al. (2001) Fluorescence detection of cervical intraepithelial neoplasia for photodynamic therapy with the topical agents 5-aminolevulinic acid and benzoporphyrin-derivative monoacid ring. Am J Obstet Gynecol 184:1164-9
Pham, T H; Hornung, R; Berns, M W et al. (2001) Monitoring tumor response during photodynamic therapy using near-infrared photon-migration spectroscopy. Photochem Photobiol 73:669-77
Liang, H; Do, T; Kasravi, S et al. (2000) Chromosomes are target sites for photodynamic therapy as demonstrated by subcellular laser microirradiation. J Photochem Photobiol B 54:175-84
Tadir, Y; Hornung, R; Pham, T H et al. (1999) Intrauterine light probe for photodynamic ablation therapy. Obstet Gynecol 93:299-303

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