COX-2 Inhibitors May Have Several Uses in Colorectal Cancer

PORTLAND, Oregon—Cyclooxygenase 2 (COX-2) inhibitors are attracting attention as potential anti-cancer drugs because of evidence of increased survival in patients with low levels of COX-2. Charles D. Blanke, MD, FACP, associate professor of medicine, Oregon Health Sciences University in Portland, reviewed current COX-2 research for participants at the Vanderbilt University symposium.

"COX-2 is constitutively expressed in only a few cells but is rapidly upregulated in response to any kind of insult," Dr. Blanke said. "COX-2 expression is increased in many tumors, including 76% of colorectal cancers [CRC]. In contrast, COX-2 expression is found in only 8% of normal colon tissue specimens. Similarly, COX-2 mRNA is increased in 86% of CRC and in over 40% of colorectal polyps. COX-2 expression in malignant cells also appears to make them act more aggressively."

Dr. Blanke said that numerous studies have assessed the effects on the development of colorectal cancer of a wide variety of nonsteroidal anti-inflammatory drugs (NSAIDS), which inhibit COX-2, and acetaminophen. "There was a consistent 50% decrease in the incidence of and mortality from colorectal cancers only in those treated with NSAIDs," he said. "There is a possible dose-response relationship, and the NSAID must be taken for a prolonged period, perhaps more than 9 years."

Logical Next Step

Given this background, attempts to combine COX-2 inhibition with chemotherapy constitute a logical next step. Work by Steinbach et al showed that treatment with celecoxib (Celebrex) reduced the polyp burden in patients with familial adenomatous polyposis (FAP), but this benefit occurred only at the 400 mg BID dose, not at the 100 mg dose.

COX-2 overexpression is significantly associated with metastasis, and transfection of COX-2 into human Caco-2 cells greatly increases their metastatic potential. Dr. Blanke said that such transfected cells express eight times more prostaglandin E than non-COX-2 transfected cells, easily degrade the extracellular matrix, and are six times more invasive. This invasiveness could be inhibited in a dose-dependent fashion by sulindac (Clinoril).

COX-2 expression has also been implicated in tumor angiogenesis. Dr. Blanke said that COX-2 is expressed in human colorectal cancer neovasculature, including liver metastases, and that expression in the neovasculature is actually greater than in the tumor cells. "Celecoxib inhibits tumor growth and spread to lungs in nude mice implanted with human colon cancer cells. The antiangiogenic properties of celecoxib lead to and are apparently responsible for the inhibition of both growth and metastases," Dr. Blanke said.

Tumor Radiosensitivity

COX-2 is also thought to play a role in survival of tumor cells after radiation therapy. Dr. Blanke said that COX-2 inhibitors enhance the efficacy of radiotherapy in mouse sarcomas. "These tumors are normally very radioresistant. The effects of COX-2 inhibition and radiation are synergistic, and treatment increases the actual cure rate. NSAIDs potentiate tumor radiosensitivity without significantly increasing normal tissue radioresponse," he said.

COX-2 expression is also associated with risk of colorectal cancer recurrence. Dr. Blanke said that COX-2 overexpression is significantly correlated with metastases, and particularly with hematogenous metastasis in patients with resected large bowel malignancies. "COX-2 overexpression is independently associated with disease-free survival, and COX-2 inhibition might be useful in preventing hematogenous metastasis," he said.

Early studies have also found that COX-2 inhibitors can increase the efficacy of cytotoxic drugs. "Mitomycin-C (Mutamycin) induces COX-2 in MKN-74 gastric cancer cells, and this induction causes cellular resistance to apoptosis. Selective COX-2 inhibition enhances mitomycin-C-induced apoptosis," Dr. Blanke said.

In vitro studies of NSCLC cells treated with irinotecan (Camptosar), docetaxel (Taxotere), etoposide (VePesid), or cisplatin (Platinol), with or without the COX-2 inhibitor nimesulide showed that the COX-2 inhibitor alone induced apoptosis at low concentrations and was "near-synergistic" for selected anticancer agents, according to Dr. Blanke. "Clinical trials should incorporate COX-2 inhibition into treatment regimens," he concluded.

Some Potential Downsides

Adding COX-2 inhibition to chemotherapy has some potential downsides, however. One is that inhibiting COX-2 might impede recovery of bone marrow after myelosuppressive treatment, since COX-2 induction is a central event in the accelerated hematopoiesis that occurs following chemotherapy.

Ongoing combination therapy trials include a phase I study of celecoxib, plus the Mayo Clinic fluorouracil (5-FU) regimen for colorectal cancer, and a phase II study of celecoxib plus trastuzumab (Herceptin) for breast cancer. Studies on the drawing board include a phase I study of rofecoxib (Vioxx)/5-FU/radiation therapy for rectal cancer, a phase I study of rofecoxib/5-FU/radiation therapy for pancreatic cancer, and a phase III study of rofecoxib as adjuvant therapy in colorectal cancer.

"Very preliminary data suggest that COX-2 inhibitors are safe combined with irinotecan, and very, very preliminary data suggest that the Saltz regimen plus celecoxib has activity in advanced colorectal cancer," Dr. Blanke noted. "COX-2 inhibition may truly shine with chemotherapy in the adjuvant setting, and future trials might also look at irinotecan plus COX-2 inhibition and radiation therapy. We suspect that these agents might decrease the diarrhea associated with irinotecan use." he said.