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Isolation and Initial Characterization of Mouse Tumor Cells Resistant to Porphyrin-mediated Photodynamic Therapy¹

Clayton Ocular Oncology Center [M.C.L., C.J.G.], Childrens Hospital of Los Angeles, and Departments of Pediatrics [C.J.G.], Radiation Oncology [C.J.G.], and Molecular Pharmacology and Toxicology [C.J.G.], University of Southern California, Los Angeles, California 90027

Photodynamic therapy (PDT)-resistant variants of the RIF-1 mouse tumor cell line have been isolated following a protocol of repeated porphyrin incubation and light treatments. Two porphyrin incubation procedures, employing either an extended (16 h) or a short (1 h) incubation, were used in order to obtain cell strains exposed to conditions with differing intracellular photosensitizer localization. Two clones from each PDT porphyrin incubation protocol were selected for in vitro and in vivo analyses based on degree of resistance and plating efficiency. Resistant variants had increased protein content and were larger than the parental RIF-1 cells. In vitro growth rates were similar for all cell strains. Both 16-h PDT-resistant variants exhibited modest resistance to ionizing radiation and one of the 16-h PDT-resistant variants demonstrated increased sensitivity to hyperthermia. The PDT-resistant variants did not exhibit a multidrug resistance phenotype nor did they have altered porphyrin uptake properties. The parental and resistant RIF cells had comparable basal levels of antioxidant enzymes, reduced glutathione and stress proteins, but the number of cells required to produce in vivo tumor growth in 50% of inoculated animals was increased for all PDT-resistant variants. The resistant cells exhibit a stable phenotype and should be useful in studies designed to define PDT mechanisms of action.

¹ This investigation was performed in conjunction with the Clayton Foundation for Research and was supported in part by USPHS Grant R37-CA-31230 awarded by the National Cancer Institute, Department of Health and Human Resources.

² To whom requests for reprints should be addressed, at Clayton Ocular Oncology Center, Childrens Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027.

Received 2/15/91. Accepted 6/ 5/91.

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