原发性高血压患者骨量减少机制初探

为探讨原发性高血压 (EH)与骨量减少的关系 ,采用双能X线骨密度仪测定了 1 2 1例肝、肾功能正常的EH患者的腰椎 (L2 ～L4 )、股骨上端的骨密度 (BMD) ;采用放免法测定血清骨钙素 (BGP)、甲状旁腺素中间片段 (PTH m) ;采用酶免法测定尿脱氧吡啶啉 (DPD)。结果 :EH病人骨密度均低于正常对照组 ,除女性≤ 4 0岁组外P均 <0 .0 1 ;血清BGP、PTH m、DPD均高于正常对照组 (P <0 .0 1 ) ;且BGP、PTH m、DPD与骨密度呈负相关 ,r分别为 -0 .30 7、-0 .2 68、-0 .2 51 (P <0 .0 1 ) ;而血清钙、磷、碱性磷酸酶与正常对照组无显著差异 (P >0 .0 5) ;男女EH病人骨量减少检出率分别为 4 4.83%及 36.50 % ,骨质疏松检出率分别为 6.90 %及 2 6.98% ,且以股骨上端华氏三角区骨量减少为著。结论 :EH病人存在钙、磷代谢紊乱 ,可导致骨量减少 ,以骨吸收大于骨形成、高骨转换为特点。提示在治疗高血压的同时应补充活性维生素D及钙剂 ,防治骨质疏松的发生。     

DPD、MTHFR和TS表达水平与氟尿嘧啶类药物治疗消化道肿瘤疗效及预后关系的研究进展

消化道恶性肿瘤包括结直肠癌、胃癌和食管癌等。尽管使用了各种治疗方式，癌症患者仍然有复发和转移。绝大多数患者确诊时即为中晚期，因而化疗在癌症患者中发挥重要作用。作为5-FU抗癌活性中的三个关键酶，二氢嘧啶脱氢酶（DPD）、5,10-亚甲基四氢叶酸还原酶（MTHFR）、胸苷酸合成酶（TS）与消化道肿瘤的疗效、对化疗药物的敏感性及患者的预后有密切关系。     

Phase II study of pharmacogenetic-tailored therapy in elderly colorectal cancer patients

Background

Retrospective analyses suggested that a pharmacogenetic approach may allow a tailored selection of chemotherapy for metastatic colorectal cancer.

Aim

We conducted a phase II study of pharmacogenetic-selected first-line chemotherapy in elderly patients with advanced colorectal cancer, with the aim to improve efficacy and to reduce toxicity in this group of patients.

Methods

24 patients were enrolled in this study. Chemotherapy regimen was prospectively assigned based on TS, DPD, ERCC-1 and UGT1A1 genotyping results. Twelve patients (50%) were treated with modified FOLFIRI, 11 patients (46%) with modified FOLFOX6 and 1 (4%) with De Gramont regimen.

Results

A partial remission was obtained in 4 cases (17%), stable disease in 8 cases (33%) and progressive disease in 12 cases (50%). Grade 3-4 neutropenia was observed in 7 patients (29%) and diarrhoea in 3 cases (12%). The trial was then interrupted according to study design requiring 13 partial remissions out of the first 24 patients enrolled as the necessary response rate level in order to continue.

Conclusion

Prospective selection of chemotherapy based on TS, DPD, ERCC-1 and UGT1A1 expression in elderly advanced colorectal cancer patients failed to confirm previous results. A more accurate validation of retrospective findings is warranted before these molecular markers can be used for treatment selection in the clinical practice.     

去卵巢骨质疏松模鼠DPD及1,25-(OH)2D3与骨质量的相关性研究

目的：探讨雌性SD大鼠切除卵巢后机体尿DPD及血1,25-（0H）2D3变化与骨质量的相关性。方法：40X雌性SD大鼠随机分为卵巢切除组（OVX组）和假手术组（Sham组）,分别于术后12、24周取材。运用双能X线骨密度仪测L1、股骨、股骨颈骨密度,ELISA法测尿DPD浓度,激素放免法测血1,25-（OH）2D3浓度,光测弹性仪测L1压缩强度极限、弹性模量及右侧股骨弯曲破坏栽荷,不脱钙骨切片技术观察胫骨上段骨组织形态结构并计量分析,对实验数据进行相关性分析。结果：术后OVX组除尿DPD／Cr明显升高外,其他检测指标均较Sham组低,且随术后时间推移持续下降,差异有统计学意义。相关分析显示：尿DPD／Cr与腰椎、股骨密度、椎体压缩强度极限、股骨弯曲破坏荷载和骨小梁面积均呈负相关。血清1,25-（OH）2D3水平与腰椎、股骨、股骨颈密度、骨小梁面积、椎体压缩强度极限和股骨弯曲破坏荷载呈正相关。结论：大鼠卵巢切除后尿DPD、血1,25-（0H）2D3水平变化与骨质量显著相关,可以通过检测尿DPD、血1,25-（0H）2D,水平变化预测骨质量。     

Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background:Previous work demonstrated that 5-fluorouracil(5-FU) metabolism is a critical factor for treatment tolerability. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability. Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria. Results:DPD activity in patients with mild toxicities (WHOgrade 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein,while in five patients with grade 3–4 gastrointestinal toxicity,DPD ranged from low to normal values (range 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe curve (AUC) was higher (range 14.70–26.20 h×µg/ml)than those observed in 84 patients with mild toxicities (CL, 56.30± 3.60 l/h/m²; AUC, 7.91 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity. Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.     

Severe 5-fluorouracil-induced toxicity due to decreased dihydropyrimidine dehydrogenase activity: report of a patient survival and urinary pyrimidine and dihydropyrimidine levels

We report a Japanese woman who survived severe 5-fluorouracil (5-FU) toxicity after receiving 5′-deoxy-5-fluoro-uridine (5′DFUR) for the treatment of breast cancer (pt2n1m1); the toxicity was due to decreased dihydropyrimidine dehydrogenase (DPD) activity. Pharmacokinetic investigation showed very high and prolonged plasma 5-FU concentrations after termination of the oral administration of 5′DFUR. The DPD activity in all plasma samples was below 30 pmol/min per mg protein. Her urinary thymine and uracil levels were high, and the ratios of urinary dihydrothymine/thymine and dihydrouracil/uracil were very low compared with the ratios in healthy people. These findings suggest that determination of urinary pyrimidine and dihydropyrimidine levels would be an appropriate urinary screening sytem that may be useful for evaluating DPD activity before 5-FU treatment is initiated. Received: January 14, 1998 / Accepted: October 29, 1998     

三种比色计在管网二氧化氯监测中的对比试验

用DR850,GDY-101和QYJ-Ⅱ型3种比色计及7230型分光光度计分别对模拟管网水中二化氯进行测定。结果表明:3种比色计对管网二氧化氯的测定结果相互间差异无显著性（P>0.05）。经比较,GDY-101型具有体积小,重量轻,结构简单,操作方便,价格低等优点,更适合于二氧化氯的现场监测。     

Biochemical markers in oncology. Part I: molecular basis. Part II: clinical uses

The investigation of the molecular mechanisms involved in carcinogenesis and tumor progression has led to the development of numerous biochemical markers. Biochemical markers may serve for early prediction of tumor recurrence, progression and development of metastases including bone metastases and for prediction of response to therapy. Tumor antigens have been used for more than a decade and although they have shown promising clinical results, their sensitivity and specificity remain limited. A lot of knowledge on the key molecules which control cell cycle, apoptosis and angiogenesis has been acquired during recent years, but their clinical value remains uncertain. Molecular markers which are linked to malignant transformation may provide a non-surgical therapeutic approach by targeting these molecules through gene therapy or antisense molecules. Because of the complexity of the physiopathogical processes involved in tumorogenesis and metastases, we first provide a review on the molecular basis of the various tumor markers and then discuss their potential clinical utility for the major cancers. The review of the current literature indicates that at the exception of a few examples, such as the use of Her-2 to predict response of the targeted Herceptin therapy, no single marker is sensitive and specific enough to perform an accurate diagnosis, predict disease progression or response to treatment. A combination of different biochemical and imaging markers appears to be the most promising strategy to monitor patients with cancer.