TP在子宫内膜癌中的表达及其临床意义

目的检测子宫内膜癌中胸苷磷酸化酶(TP)的表达情况,探讨它与子宫内膜癌预后的相关性及临床意义。方法采用免疫组化SP法检测15例正常内膜,10例不典型增生内膜,48例子宫内膜癌石蜡标本中的TP蛋白表达情况。结果子宫内膜癌TP表达显著高于正常内膜(PTP=0.029)。TP表达与肿瘤分化程度、浸润深度、淋巴结转移及临床病理分期无相关性(P>0.05)。结论 TP的过度表达可能与子宫内膜癌的预后有关。     

线粒体神经胃肠型脑肌病的临床和病理分析

目的 探讨线粒体神经胃肠型脑肌病(Mitochondrial Neurogastrointestinal Encephalopathy Disease,MNGIE)的临床和病理特点.方法 通过1例临床确诊为线粒体神经胃肠型脑肌病病例的临床表现、影像学检查及病理检查,系统回顾线粒体神经胃肠型脑肌病的发病机制、临床表现、病理特点.结果 该患有长期的腹痛、腹泻史,神经系统首发症状为听力障碍,此后出现头晕、走路不稳、记忆力逐渐下降.神经系统检查有眼外肌麻痹、听力障碍、周围神经损害.肌电图:广泛神经源性损害.头部MRI表现为广泛的白质脑病.肌肉活检为HE染色中出现嗜碱的肌纤维,在GT染色中为典型和不典型的RRF,在NADH染色和SDH染色中深染.结论 线粒体神经胃肠型脑肌病是一种特殊类型的线粒体肌病,具有上述临床及影像学特点,加上血及(或)脑脊液乳酸水平升高,肌肉活检示组织学线粒体肌病的表现.如果发现血清白细胞中胸苷磷酸化酶活性降低或基因检测发现胸苷磷酸化酶(thymidine phosphorylase,TYMP)基因位点突变更能进一步确诊.     

TS、TP及DPD表达与乳腺癌新辅助化疗的关系

目的 检测乳腺癌标本中胸苷酸合成酶（Thymidylate Synthase,TS）、胸腺嘧啶脱氧核苷磷酸化酶（Thymidine Phosphorylase,TP）、二氟嘧啶脱氢酶（Dihydropyrimidine Dehydrogenase,DPD）表达状况,评价TS、TP、DPD的表达与新辅助化疗效果之间的关系.方法 选择81例可手术的乳腺癌患者,手术前均接受CMF方案新辅助化疗,采用免疫组织化学染色的方法对新辅助化疗前麦默通活检系统切取的乳腺癌组织中TS、TP和DPD的表达进行检测.结果 TS、TP阴性患者的部分缓解率要明显高于阳性患者,而DPD阳性患者的部分缓解率明显高于阴性患者,差异具有统计学意义（P＜0.05）;DPD阴性患者Ⅲ～Ⅳ度毒副反应发生率高于阳性患者（P＜0.05）,而TS、TP的表达水平与化疗所产生的毒副反应之间无明显关系（P＞0.05）.结论 TS、TP及DPD的表达与乳腺癌患者接受CMF方案的新辅助化疗的治疗效果相关,而DPD的表达则与含5-FU类化疗药物所产生的毒副反应相关.     

Cytokines Induce Uridine Phosphorylase in Mouse Colon 26 Carcinoma Cells and Make the Cells More Susceptible to 5'-Deoxy-5-fluorouridine

The antiproliferative activity of 5-fluorouracil (5-FUra) and 5'-deoxy-5-fluorouridine (5'-dFUrd), used in combination with typical cytokines and growth factors, was investigated in mouse colon 26 carcinoma cells. Tumor necrosis factor α (TNFα), interleukin-1a (IL-1α), and interferon γ (IFNγ) at low doses showing < 50% inhibition of cell growth by themselves enhanced the susceptibility of the cells to the activity of 5'-dFUrd. In particular, a mixture of these cytokines greatly enhanced the activity of 5'-dFUrd and 5-FUra by up to 12.4- and 2.7-fold, respectively, whereas the activity of other cytostatics was only slightly changed (< 1.5-fold). Basic fibroblast growth factor also increased the susceptibility, but only to 5'-dFUrd. This preferential enhancement of the activity of 5'-dFUrd would be due to induction by the cytokines of uridine phosphorylase (Urd Pase), by which 5'-dFUrd is converted to 5-FUra. TNFα, IL-1α, IFNγ, and a mixture of these factors increased the enzyme activity by up to 3.7-fold in colon 26 cells. Consequently, the anabolism of 5'-dFUrd to fluoronucleotides and the incorporation of 5-FUra into RNA in colon 26 cells were increased by TNFα treatment. In addition, the increase by the cytokine mixture in the susceptibility to 5'-dFUrd was abolished by an inhibitor of Urd Pase, 2,2'-anhydro-5-ethyluridine. These results indicate that induction of Urd Pase activity by cytokines is a critical event that increases the susceptibility to 5'-dFUrd.     

Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine: relevance to uridine rescue in chemotherapy

Purpose: The purpose of this investigation was to study the effects of combining oral 5-(phenylselenenyl)acyclouridine (PSAU) with 2′,3′,5′-tri-O-acetyluridine (TAU) on the levels of plasma uridine in mice. PSAU is a new lipophilic and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. PSAU has 100% oral bioavailability and is a powerful enhancer of the bioavailability of oral uridine. TAU is a prodrug of uridine and a far superior source of uridine than uridine itself. Methods: Oral TAU was administered to mice alone or with PSAU. The plasma levels of uridine and its catabolites as well as PSAU were measured using HPLC and pharmacokinetic analysis was performed. Results: Oral administration of 2000 mg/kg TAU increased plasma uridine by over 250-fold with an area under the curve (AUC) of 754 μmol · h/l. Coadministration of PSAU at 30 and 120 mg/kg with TAU further improved the bioavailability of plasma uridine resulting from the administration of TAU alone by 1.7- and 3.9-fold, respectively, and reduced the C_max and AUC of plasma uracil. Conclusion: The exceptional effectiveness of PSAU plus TAU in elevating and sustaining a high plasma uridine concentration could be useful in the management of medical disorders that are remedied by administration of uridine, as well as the rescue or protection from host toxicities of various chemotherapeutic pyrimidine analogues. Received: 10 November 1999 / Accepted: 14 March 2000     

Role of growth hormone in regulation of polynucleotide-phosphorylase activity in rat liver

Hypophysectomy in rats is followed by a significant increase in polynucleotide-phosphorylase (PNPase) activity in ribosomal fractions of the liver. Injection of growth hormone into hypophysectomized animals leads to inhibition of PNPase activity. Within the dose range from 5 to 100 g the dose—effect curve is linear. The action of growth hormone is most marked 18h after a single injection.Laboratory of Enzymology, Academy of Medical Sciences of the USSR, and Laboratory of Biological Standardization of Hormones, Institute of Experimental Endocrinology and Hormone Chemistry, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 2, pp. 162–163, February, 1980.     

Thymidine phosphorylase expression is preserved after radiotherapy in patients with cervical squamous cell carcinoma

Purpose The aim of this study was to investigate the changes in two of the enzymes involved in fluorouracil metabolism, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), in uterine cervical squamous cell cancer tissue after radiotherapy.Subjects and methods Cervical tissue from 27 patients diagnosed with stage IIIB or IV uterine cervical squamous cell cancer was compared with normal cervical tissue from 33 patients with benign gynecologic diseases. Expression of TP and DPD in the cervical tissues was measured using enzyme-linked immunosorbent assays. TP and DPD expression before and after irradiation with 10 and 20 Gy was measured in 9 of the 27 patients with cervical cancer.Results Before irradiation, DPD expression in cancer tissue did not differ from that in normal tissue. TP expression and the TP/DPD ratio were significantly higher in cancer tissue than in normal tissue (P<0.00001). TP and DPD expression and the TP/DPD ratio were not significantly changed by irradiation with 10 and 20 Gy. TP expression and the TP/DPD ratio after irradiation with 10 and 20 Gy were significantly higher than in normal tissue.Conclusion The increased TP expression and the elevated TP/DPD ratio following irradiation with up to 20 Gy may offer an increased clinical advantage to chemoradiotherapy with capecitabine or doxyfluridine over radiotherapy alone.     

Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor,RO0094889

Capecitabine is an orally available fluoropyrimidine and is finally converted to 5-FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD-overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5-vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5-ethynyluracil or 5-vinyluracil, which inhibited DPD not only in tumor tissues but also in other non-cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD.