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For the first time it has been shown that a COX-2 inhibitor may boost the effectiveness of chemotherapy in the treatment of cancer, according to a study by physician-scientists at NewYork Weill Cornell Medical Center. The new study, which looks at Non-Small Cell Lung Cancer (NSCLC), represents the latest of numerous Weill Cornell research findings suggesting the benefits of COX-2 inhibitors for treatments of cancer and pre-cancerous conditions of the lung, colon, breast, esophagus, mouth, and bladder. NSCLC is the most aggressive type of lung cancer and the leading cause of cancer death in the U.S.

The new study, published in the current issue of the Journal of Clinical Oncology, finds that patients with NSCLC treated with celecoxib, a COX-2 inhibitor, administered in conjunction with paclitaxel and carboplatin, two common chemotherapeutic agents, results in lower levels of intratumoral prostaglandin E2 (PGE2), a molecule associated with tumor growth, when compared to treatment with chemotherapy alone. Additionally, the treatment is shown to be feasible and safe.

"This study shows that celecoxib, by decreasing COX-2-derived PGE2, may be useful when given in combination with chemotherapy," said Dr. Nasser Altorki, the study's principal investigator, Professor of Cardiothoracic Surgery at Weill Cornell Medical College, and Director of the Division of Thoracic Surgery at NewYork Weill Cornell Medical Center. "Remarkably, for patients taking celecoxib, the amount of PGE2 present in the tumor was equivalent to amounts in a non-cancerous lung."

During the Phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, along with daily doses of 800 mg of celecoxib, followed by surgical resection of the tumor. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared with 13 control patients, who received paclitaxel and carboplatin without celecoxib. Overall clinical response rate was 65 percent.

An upcoming multicenter Phase II trial led by Dr. Altorki will examine changes in tumor size and survival rates for NSCLC patients treated with chemotherapy alone vs. chemotherapy plus a COX-2 inhibitor (celecoxib).

Cyclooxygenase-2 (COX-2) is an enzyme that catalyzes the synthesis of prostaglandins (PGs). Increased levels of COX-2 and PGs have been observed in a variety of malignancies including NSCLC. PGE2, a downstream product of COX-2, can promote tumor growth by stimulating angiogenesis and invasiveness, as well as inhibiting apoptosis (cell death) and immune surveillance. Additionally, higher-than-normal quantities of COX-2 may unfavorably alter the response of malignant cells to cytotoxic therapy. Similarly, paclitaxel treatment induces high quantities of COX-2.

The study was supported by a grant from Pharmacia Oncology and Pfizer. Preliminary results were first presented at the annual meeting of the American Society of Clinical Oncology in April 2002.

The study is co-authored by Dr. Andrew Dannenberg, Co-Director of NewYork-Presbyterian Hospital's Cancer Prevention Program and the Henry R. Erle-Roberts Family Professor of Medicine at Weill Cornell Medical College. Contributing authors from NewYork Weill Cornell Medical Center include Dr. David Yankelevitz, Dr. Kotha Subbaramaiah, Dr. Jeffrey Port, Dr. Roger Keresztes, Dr. Robert Korst, Dr. Douglas Flieder, Dr. Daniel Libby, Dr. Mark Pasmantier, and Cathy Ferrara, R.N.

NewYork Weill Cornell's COX-2 Anti-Cancer Research

For the last decade, NewYork Weill Cornell's Dr. Andrew Dannenberg has led research on the use of COX-2 inhibitors for a range of cancer and pre-cancerous conditions. Ongoing research is evaluating the potential utility of selective COX-2 inhibitors in conditions including:

• Pre-cancerous adenomatous polyps of the colon
• Basal cell (skin) carcinomas in patients with the nevoid basal cell carcinoma syndrome
• Barrett's esophagus, a pre-cancerous condition of the esophagus
• Non-small-cell lung cancer
• Oral pre-malignant lesions, white and red patches in the oral cavity that are commonly caused by tobacco and alcohol use
• Cancer of the bladder

Other investigations are studying how dietary constituents that inhibit COX-2 — such as resveratrol (found in red wine and the skin of red grapes), and omega-3 fatty acids (found in fish like salmon) — can prevent cancer.

Celecoxib and COX-2

Studies have shown that levels of COX-2 are markedly elevated in many different types of cancer versus adjacent normal tissue. Celecoxib, an anti-inflammatory drug commonly used to treat arthritis, has been shown to inhibit COX-2, and in turn, reduce the formation, growth and metastasis of several types of experimental cancers. Celecoxib also has been shown to suppress angiogenesis, the process by which tumors create new blood vessels needed to obtain nutrients for their growth and spread.

Additionally, because standard cancer therapies like chemotherapy and radiation induce COX-2, selective COX-2 inhibitors such as Celecoxib may prove useful as a supplemental, or adjuvant, therapy. In 1999, the drug was approved by the FDA for use to reduce the number of polyps in familial adenomatous polyposis (FAP), a rare and devastating genetic condition that results in colorectal cancer.