No abstract

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in prostaglandin (PG) synthesis and is overexpressed in 70% to 90% of non^small cell lung cancers (NSCLC). Preclinical studies suggest inhibition of COX-2 can enhance the cytotoxic effect of docetaxel. To test this concept clinically, we administered celecoxib (400 mg p.o. twice daily) plus docetaxel (75 mg/m 2 every 3 weeks) to a cohort of patients with recurrent, previously treated NSCLC. Patients first received single agent celecoxib for 5 to 10 days to ascertain the effectiveness of COX-2 inhibition, which was determined by measuring pre-and post-celecoxib levels of urinary 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E 2 (PGE 2 ). We enrolled 56 patients (35 men, 21women; median age, 61years). All patients had received at least one prior chemotherapy regimen. The overall response rate was 11% and median survival was 6 months, similar to that observed with docetaxel alone. Pre-celecoxib urinary PGE-M decreased from a mean level of 27.2 to 12.2 ng/mg Cr after 5 to 10 days of celecoxib (P = 0.001).When grouped by quartile, patients with the greatest proportional decline in urinary PGE-M levels experienced a longer survival compared to those with no change or an increase in PGE-M (14.8 versus 6.3 versus 5.0 months). Our data suggest that combining celecoxib with docetaxel using the doses and schedule employed does not improve survival in unselected patients with recurrent, previously treated NSCLC. However, in light of the apparent survival prolongation in the subset with a marked decline in urinary PGE-M levels, further investigation of strategies designed to decrease PGE 2 synthesis in NSCLC seems warranted.Cyclooxygenase-2 (COX-2), a cyclic endoperoxidase that catalyzes the rate-limiting step in prostaglandin (PG) synthesis, is frequently overexpressed in human premalignant pulmonary lesions such as atypical adenomatous hyperplasia and carcinoma in situ, as well as in invasive carcinomas (1 -4). Preclinical and clinical data indicate that tumors with up-regulation of COX-2 synthesize high levels of prostaglandin E 2 (PGE 2 ; refs. 5 -11). In turn, high PGE 2 levels are associated with increased production of proangiogenic factors, altered immune responses, and enhanced metastatic potential (12 -16). These findings suggest that increased COX-2 expression may play a significant role in the development and growth of malignancies, such as nonsmall cell lung cancers (NSCLC), and possibly in the acquisition of an invasive and metastatic phenotype (17, 18). Thus, selective inhibition of COX-2 could prove useful both in understanding the role of eicosanoids in lung cancer pathogenesis as well as in the management of established malignancies (19,20).Docetaxel is modestly beneficial in the treatment of recurrent NSCLC (21). Notably, recent preclinical data indicate that the cytotoxic effect of docetaxel is enhanced in the presence of a selective COX-2 inhibitor (22). Based on these find...

Purpose: Increased levels of cyclooxygenase-2 and prostaglandin E 2 (PGE 2 ) have been observed in tobacco-related malignancies of the upper aerodigestive tract. Moreover, exposure to tobacco smoke can stimulate the synthesis of PGE 2 . Recent evidence suggests that urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE 2 production. In this study, we investigated whether levels of urinary PGE-M were increased in smokers and in patients with head and neck squamous cell carcinoma (HNSCC). Experimental Design: Fifty-eight HNSCC cases and 29 age-and gender-matched healthy controls were prospectively enrolled in the study. A detailed smoking history and single void urine specimen were obtained from each participant. Levels of urinary PGE-M were quantified in a blinded fashion using mass spectrometry and compared with smoking history and tumor status. Results: Adjusted for case-control matching, median urinary PGE-M levels were significantly higher in ever smokers (15.7 ng/mg creatinine) compared with never smokers (9.9 ng/mg creatinine) for the entire study population (n = 87, P = 0.005). Concentrations of urinary PGE-M were nearly doubled in ever smokers (15.2 ng/mg creatinine) versus never smokers (7.8 ng/mg creatinine) among healthy controls (P = 0.001). Higher PGE-M levels were observed in current versus former smokers and in those with greater pack-year exposure. A significant difference in amounts of PGE-M was not observed in patients with HNSCC versus healthy controls. Conclusions: Increased levels of urinary PGE-M were observed in smokers. Urinary PGE-M may have use as a noninvasive biomarker of the effects of tobacco smoke exposure.

1969). Brit. J. industr. Med., 26,[202][203][204][205][206][207][208][209][210][211][212][213][214][215][216]. An investigation of lead absorption in an electric accumulator factory with the use of personal samplers. Thirty-nine lead workers and controls, in stable conditions of exposure, each wore personal lead-in-air samplers daily for two weeks. During the second week samples for blood lead, urinary lead, urinary coproporphyrin, urinary 8-aminolevulinic acid (ALA), the punctate basophil count, and haemoglobin were taken daily. Duplicate estimations were made on one day.The lead exposures of men doing almost identical jobs differed by ratios of up to four to one. This could be attributed only to personal differences in working habits.The correlation coefficients and regression equations of the biochemical tests with lead-inair and with each other were determined. The-mean values and 95 % confidence limits of single determinations of some of the biochemical tests corresponding to the two commonly accepted TLVs of lead-in-air (0-20 and 0 15 mg./m.3) were calculated from the regression equations.For each biochemical test the variation due to analytical error, the variation from day to day within subjects and the residual variation about the regression on lead-in-air were calculated. Previous estimates of the latter are not known. Excessive confidence may be placed in an index of exposure due to its low coefficient of variation within subjects unless the coefficient of variation between subjects about regression is taken into account.The correction for specific gravity of estimations of lead and ALA in spot samples of urine was found to reduce slightly the residual variation between subjects about the regression on lead-in-air and to increase the correlations with lead-in-air and with the other biochemical tests, but these changes were not statistically significant.The modified method used for estimating blood lead and urinary lead is described and validated.