Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients

Purpose: Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. Methods: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m² of capecitabine twice daily p.o. for 5–7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. Results: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P=0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P=0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. Conclusions: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5′-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues. Received: 4 June 1999 / Accepted: 28 October 1999     

卡培他滨联合伊立替康同步治疗转移性结直肠癌

目的探讨卡培他滨联合伊立替康治疗转移性结直肠癌患者的近期疗效和不良反应。方法对40例转移性结直肠癌患者给予卡培他滨1250mg/m2/d分早晚服用,连服14d,伊立替康200mg/m2,化疗第1天静脉注射,21d为一周期。结果 40例患者中,其中一例因呼吸衰竭死亡,39例进行疗效评价。完全缓解(CR)0例,部分缓解(PR)21例,稳定(SD)10例,进展(PD)8例,总有效率53.8%,临床控制率79.5%。结论卡培他滨联合伊立替康治疗转移性结直肠癌疗效好,不良反应患者可以耐受。     

XELOX方案联合小牛脾注射液治疗老年晚期胃癌的疗效观察

目的 探讨卡培他滨和奥沙利铂(XELOX方案)联合小牛脾注射液治疗老年晚期胃癌的临床效果及对血清甲状腺转录因子-1(TTF-1)和肿瘤特异性生长因子(TSGF)水平的影响.方法 选取2018年12月至2020年12月间郑州市第二人民医院收治的76例老年晚期胃癌患者,采用抛硬币法分为观察组和对照组,每组38例.对照组患者...     

周剂量多西他赛联合卡培他滨治疗晚期胃癌的疗效观察

目的观察周剂量多西他赛联合卡培他滨治疗晚期胃癌的疗效及不良反应。方法多西他赛每次剂量25mg·m-2,d1、d8、d15,卡培他滨每日2000mg·m-2,分2次口服,d1～d14,28天为1周期,连用2周期以后评价疗效。结果 40例晚期胃癌患者均可评价疗效,其中完全缓解0例(0%),部分缓解18例(45.0%),病情稳定16例(40.0%),病情进展6例(15.0%),总有效率为45.0%,中位疾病无进展时间(TTP)为6.35月。不良反应多为骨髓抑制、胃肠道反应、手足综合征,严重不良反应主要为白细胞下降(35%)。结论周剂量多西他赛联合卡培他滨治疗晚期胃癌近期疗效好,严重不良反应少,患者耐受性高,可改善患者的生存质量。     

内镜介入注射卡培他滨治疗老年胃癌患者的临床疗效观察

目的观察内镜介入注射卡培他滨治疗老年胃癌的临床疗效。方法选择我院收治的老年胃癌患者32例并将其随机分为对照组与观察组,每组16例,对照组患者给予紫杉醇常规化疗,观察组患者采用内镜介入注射卡培他滨治疗,剂量2000mg·m-2·d-1,分早晚2次,餐后30min口服,21d为1周期,每例患者最少2个周期,最多6个周期,平均3个周期。采用ACCESS2化学发光免疫分析系统检测患者血清CEA、AFP、CA19-9、CA72-4水平。结果对照组患者部分缓解(PR)4例,疾病稳定(SD)3例,疾病进展(PD)9例,有效率25%,获益率43.8%;而观察组患者部分缓解(PR)6例,疾病稳定(SD)5例,疾病进展(PD)5例,有效率37.5%,获益率68.8%,显著高于对照组。治疗后,观察组患者血清CRP水平降低缓慢或不降低,对照组患者迅速到至正常水平,两组阳性率无明显差异(P>0.05);对照组患者血清AFP、CEA、CA19-9、CA72-4的阳性率均明显高于观察组(P<0.05)。两组患者用药后均出现不同程度的不良反应,其中常规组中出现较严重的手足综合征4例、口腔炎2例、腹泻1例,其中需要住院治疗2例;而观察组不良反应的程度较轻。结论内镜介入注射卡培他滨治疗老年性晚期胃癌疗效明显且毒副反应较小,并可显著降低多种肿瘤标记物的水平。     

鸦胆子油乳注射液联合CapeOx方案治疗早发型结肠癌的临床研究

目的 探讨鸦胆子油乳注射液联合CapeOx方案治疗早发型结肠癌的临床疗效。方法 选取2017年6月—2021年5月徐州医科大学附属连云港医院收治的96例早发型结肠癌患者，按随机数字表法将所有患者分为对照组和治疗组，每组各48例。对照组患者给予CapeOx方案化疗，化疗第1～14天餐后30 min口服卡培他滨片，1 g/m²，2次/d；第1天静脉滴注注射用奥沙利铂，130 mg/m²加入5%葡萄糖注射液250 mL中后给药，1次/d，每次滴注2 h。治疗组在对照组治疗基础上化疗第1～14天静脉滴注鸦胆子油乳注射液，30 mL/次加入0.9%氯化钠注射液250 mL中后给药，1次/d。两组均以21 d为1个周期，且均连续治疗2个周期。观察两组的临床疗效，比较治疗前后两组血清肿瘤标志物[癌胚抗原（CEA）、糖类抗原（CA）199、CA72-4、CA50]和血管内皮生长因子（VEGF）水平、大肠癌患者生命质量测定量表（FACT-C）评分。统计两组不良反应情况。结果 治疗后，治疗组客观缓解率（ORR）是47.92%，较对照组的35.42%有所提高，但差异无统计学意义；治疗组疾病控制率（DCR）是87.50%显著高于对照组的70.83%（P＜0.05）。治疗后，两组FACT-C中生理状况评分、情感状况评分、附加关注领域评分及量表总评分均显著增加（P＜0.05）；且均以治疗组患者增加更显著（P＜0.05）；功能状况和社会/家庭状况领域评分组内治疗前后及组间同期比较差异均无统计学意义。治疗后，两组血清CEA、CA199、CA72-4、CA50和VEGF水平均显著下降（P＜0.05）；均以治疗组降低更显著（P＜0.05）。治疗过程中，治疗组白细胞减少、肝肾损害、血小板减少的发生率分别为18.75%、10.42%、14.58%，显著低于对照组的37.50%、27.08%、33.33%（P＜0.05）。结论 鸦胆子油乳注射液联合CapeOx方案治疗早发型结肠癌具有一定的增效减毒作用，能有效提高患者近期疗效、下调血清肿瘤标志物水平及抑制肿瘤血管生成，并提高化疗耐受性，改善患者生命质量，值得临床推广应用。     

Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1^–/–) mice, and a hepatic human CES1 transgenic model in the Ces1^–/– background (TgCES1). Ces1^–/– mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1^–/– mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1^–/– mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1^–/– and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.