Cyclooxygenase-2 inhibitor treatment enhances photodynamic therapy-mediated tumor response.
Photodynamic therapy (PDT) continues to be used in the treatment of solid tumors. Clinical results are promising, but the therapy has not been optimized, and tumor recurrences can occur. Recently, it has been shown that inhibitors of cyclooxygenase (COX)-2 can be effective in combination with conventional chemotherapy and radiation therapy. In the current study, we examined the parameters of PDT-mediated activation of COX-2 expression. We also examined the tumoricidal effectiveness of combining PDT with the selective COX-2 inhibitor NS-398. PDT induced the transcriptional activation of COX-2. Prolonged expression of COX-2 protein was observed in PDT-treated mouse sarcoma and carcinoma cell lines, whereas COX-1 was not inducible by PDT. Prostaglandin (PG) E2 synthesis was also increased in PDT-treated cells, and PGE2 levels were attenuated in cells coincubated with NS-398, indicating that PDT induced the expression of biologically active COX-2. Both porphyrin- and chlorin-based photosensitizers were able to elicit PDT-mediated COX-2 expression. COX-2 was also elevated in radiation-induced fibrosarcoma (RIF) tumors after treatment with PDT. We also observed that systemic administration of NS-398 decreased PDT induction of both PGE2 and vascular endothelial growth factor in treated RIF tumors. Additionally, we demonstrated that NS-398 enhanced PDT responsiveness in RIF tumors without increasing toxicity to normal tissue. These results provide strong evidence that combination procedures involving selective COX-2 inhibitors may improve the therapeutic effectiveness of PDT.
Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
Angela
A
Ferrario
Karl
K
Von Tiehl
Sam
S
Wong
Marian
M
Luna
Charles J
CJ
Gomer
D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology*; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D009578:Nitrobenzenes / Q000494:pharmacology*; D010778:Photochemotherapy / Q000379:methods*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse