Effect of combined cyclooxygenase-2 and matrix metalloproteinase inhibition on human sarcoma xenografts.
OBJECTIVE
Sarcomas express cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity. COX-2 inhibition is efficacious against many cancer types but has not been tested for human sarcomas. Matrix metalloproteinase (MMP) inhibitors also possess antiproliferative activity. Because MMP inhibitor therapy induces COX-2 expression, the authors hypothesized that the combination of COX-2 and MMP inhibitors results in a synergistic antitumor effect.


METHODS
Human osteosarcoma or rhabdomyosarcoma cells were injected into athymic mice. Tumor development and growth were measured following treatment with a COX-2 inhibitor (celecoxib), an MMP inhibitor (doxycycline), or both. The tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels.


RESULTS
When treatment was started prior to tumor cell implantation, doxycycline inhibited osteosarcoma tumor growth alone and in combination with celecoxib (30% and 33% reduction, respectively). An effect on osteosarcoma tumor implantation rates was noted in mice receiving doxycycline alone and in combination with celecoxib (12.5% and 6.25% reduction, respectively). Established osteosarcoma and rhabdomyosarcoma tumors were inhibited only by combination therapy (36% and 55%, respectively). A higher proportion of osteosarcoma tumors in the combination therapy group had more than 50% necrosis (3/7) when compared with control tumors (0/8). Antitumor effects did not correlate with PGE2 levels, suggesting the observed interaction with doxycycline was due to previously described non-enzymatic effects of celecoxib.


CONCLUSIONS
The authors' preclinical data suggest that the combination of inexpensive, nontoxic, oral COX-2 and MMP inhibitors may be useful for the treatment of some types of solid tumors.
Dickens
David S
DS
Division of Pediatric Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Ohio 45229, USA.
Cripe
Timothy P
TP
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000096:biosynthesis; D004318:Doxycycline / Q000008:administration & dosage; D004334:Drug Administration Schedule; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases; D011480:Protease Inhibitors / Q000008:administration & dosage; D011720:Pyrazoles; D018233:Rhabdomyosarcoma, Embryonal / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020778:Matrix Metalloproteinase 2; D000068579:Celecoxib; D015232:Dinoprostone; D004318:Doxycycline