Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice.
OBJECTIVE
The aim of the present study was to potentiate the antitumor effectiveness of photodynamic therapy (PDT). A cDNA microarray analysis was used to evaluate the gene expression pattern after Photofrin-mediated PDT to find more effective combination treatment with PDT and inhibitor(s) of the identified gene product(s) overexpressed in tumor cells.


METHODS
Atlas Mouse Stress Array was used to compare the expression profile of control and PDT-treated C-26 cells. The microarray results have been confirmed using Western blotting. Cytostatic/cytotoxic in vitro assay as well as in vivo tumor models were used to investigate the antitumor effectiveness of PDT in combination with cyclooxygenase (COX) 2 inhibitors.


RESULTS
PDT induced the expression of 5 of 140 stress-related genes. One of these genes encodes for COX-2, an enzyme important in the tumor progression. Inhibition of COX-2 in vitro with NS-398, rofecoxib, or nimesulide, or before PDT with nimesulide did not influence the therapeutic efficacy of the treatment. Administration of a selective COX-2 inhibitor after PDT produced potentiated antitumor effects leading to complete responses in the majority of treated animals.


CONCLUSIONS
COX-2 inhibitors do not sensitize tumor cells to PDT-mediated killing. However, these drugs can be used to potentiate the antitumor effectiveness of this treatment regimen when administered after tumor illumination.
Makowski
Marcin
M
Departments of Immunology, The Medical University of Warsaw, Warsaw, Poland.
Grzela
Tomasz
T
Niderla
Justyna
J
ŁAzarczyk
Maciej
M
Mróz
Paweł
P
Kopeé
Maciej
M
Legat
Magdalena
M
Strusińska
Katarzyna
K
Koziak
Katarzyna
K
Nowis
Dominika
D
Mrówka
Piotr
P
Wasik
Maria
M
Jakóbisiak
Marek
M
Gołab
Jakub
J
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017323:Dihematoporphyrin Ether / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008027:Light; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D010778:Photochemotherapy; D011451:Prostaglandin-Endoperoxide Synthases; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D017323:Dihematoporphyrin Ether; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases