Chemotherapy Induces the Expression of Cyclooxygenase-2 in Non–Small Cell Lung Cancer

Abstract

Purpose: To determine the effect of taxane-based chemotherapy on intratumoral levels of cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ) in patients with non^small cell lung cancer (NSCLC). Experimental Design: Lung specimens obtained at the time of surgery were used to measure levels of COX-2 and PGE 2 in tumors and adjacent nontumorous tissues in three subsets of NSCLC patients who underwent: (A) surgical resection only (n = 16); (B) surgical resection after preoperative taxane-based chemotherapy (n = 13); or (C) surgical resection after preoperative chemotherapy coadministered with the selective COX-2 inhibitor, celecoxib 400 mg bid (n = 17). Results: Levels of intratumoral PGE 2 were nearly 3-fold higher among patients who received preoperative chemotherapy compared with those treated by surgery alone (P < 0.001). This difference was abrogated by the addition of celecoxib to preoperative chemotherapy (P < 0.001).Amounts of intratumoral COX-2 were f3-fold higher in groups of patients who received preoperative chemotherapy with celecoxib (P < 0.0001) or without celecoxib (P < 0.001), compared with the group who underwent surgical resection only. Importantly, statistically significant positive correlations between COX-2 and PGE 2 were observed in the surgery only (r = 0.502, P = 0.047) and preoperative chemotherapy groups (r = 0.740, P = 0.004); this correlation was abrogated when celecoxib was given with chemotherapy (r = 0.005, P = 0.98). Conclusions: Treatment with chemotherapy led to increased amounts of COX-2 and PGE 2 in NSCLC. Cotreatment with celecoxib abrogated the increase in levels of PGE 2 but not COX-2 induced by chemotherapy. Importantly, these results clearly show that levels of a pharmacologic target (i.e., COX-2) can be affected by both the intrinsic molecular properties of a tumor and therapy.

Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in Patients With Biomarker-Selected Non–Small-Cell Lung Cancer

“…Taxanes have been documented to stimulate COX-2 expression. 1 In fact, the use of a COX-2 inhibitor has been suggested as a method to overcome this issue. This hypothesis is supported by several negative studies that have investigated COX-2 suppression plus chemotherapy in NSCLC.…”

“…In early-stage NSCLC, treatment with celecoxib can modulate the increased expression of COX-2-dependent prostaglandin E2 (PGE2) in tumor tissue after neoadjuvant treatment. 1 Several studies have demonstrated that the addition of COX-2 inhibitors to standard…”

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…COX-2 may positively affect multiple processes, including tumour cell growth, migration and invasiveness, but may also downregulate apoptosis and angiogenic stimulation (35)(36)(37)(38). Moreover, the overexpression of COX-2 may also reduce the response of cancer cells to cytotoxic therapy (140). Preclinical studies suggested that treatment with NSAIDs, particularly COX-2 inhibitors, may affect the outcome of chemotherapy through various mechanisms, including the inhibition of neoangiogenesis and the induction of apoptosis (130,131,141).…”

Phase II Trial of a Metronomic Schedule of Docetaxel and Capecitabine with Concurrent Celecoxib in Patients with Prior Anthracycline Exposure for Metastatic Breast Cancer

“…Studies using cultured monocytes and macrophages indicate that exposure to taxanes may actually stimulate expression of Cox-2 35 . That observation is supported by data from a study involving lung cancer patients treated with preoperative taxane-based chemotherapy 36 . It should also be noted that the anti-inflammatory properties of celecoxib may reduce the severity of some of the common toxicities of docetaxel and capecitabine, namely arthralgias and hand-foot syndrome.…”