Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: A phase II trial of celecoxib and docetaxel
Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: A phase II trial of celecoxib and docetaxel
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DOI：
10.1158/1078-0432.ccr-05-0436
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发表时间：
2005-09-15
影响因子：
11.5
通讯作者：
Johnson, DH
中科院分区：
文献类型：
--
作者：
Csiki, I;Morrow, JD;Johnson, DH
环加氧酶-2 (COX-2) 催化前列腺素 (PG) 合成中的限速步骤，并且在 70% 至 90% 的非小细胞肺癌 (NSCLC) 中过度表达。临床前研究表明抑制COX-2可以增强多西紫杉醇的细胞毒作用。为了在临床上检验这一概念，我们对一组既往治疗过的复发性 NSCLC 患者给予塞来昔布（400 mg，口服，每日两次）加多西他赛（75 mg/m(2)，每 3 周）。患者首先接受塞来昔布单药治疗 5 至 10 天，以确定 COX-.2 抑制的有效性，这是通过测量塞来昔布前后尿 11 α-羟基-9,15-dioko2,3,4,5-四去甲-前列腺素-1,20-二酸 (PGE-M)（前列腺素 E-2 (PGE(2)) 的主要代谢物）水平来确定的。我们招募了 156 名患者（35 名男性，21 名女性；中位年龄 61 岁）。所有患者之前均接受过至少一种化疗方案。总体缓解率为 11%，中位生存期为 6 个月，与单独使用多西紫杉醇观察到的情况相似。塞来昔布治疗前 5 至 10 天后，尿 PGEM 平均水平从 27.2 ng/mg Cr 下降至 12.2 ng/mg Cr（P = 0.001）。按四分位数分组时，尿 PGEM 水平下降比例最大的患者与 PGE-M 没有变化或增加的患者相比，生存期更长（14.8 个月与 6.3 个月与 5.0 个月）。我们的数据表明，使用所采用的剂量和方案将塞来考昔与多西紫杉醇联合使用并不能改善未经选择的复发性、既往治疗过的 NSCLC 患者的生存率。然而，鉴于该亚群的生存期明显延长，尿 PGE-M 水平显着下降，似乎有必要进一步研究旨在减少 NSCLC 中 PGE(2) 合成的策略。
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 clini- cally, 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 11 alpha-hydroxy-9,15-dioko2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M),the major metabolite of prostaglandin E-2 (PGE(2)). We enrolled 156 patients (35 men, 21 women; median age, 61 years). 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 PGEM 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 PGEM 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.