体内诱导艾氏腹水瘤细胞的耐药性研究

肿瘤细胞耐药性的存在是临床化疗失败的主要原因之一。本实验在小鼠体内用阿霉素（ADR）诱导艾氏腹水瘤细胞（EHR）的耐药性，探讨细胞产生耐药性的机理。HPLC法测定细胞内药物浓度．结果表明耐药细胞─—EHR/ADR细胞内ADR积聚低于EHR细胞，而对ADR外排快于EHR细胞；异博定（VER）增加EHR／ADR细胞对ADR的摄取并阻滞其外排．而对EHR影响不大，揭示EHR／ADR细胞具有MDR特性。     

MNP和MVP方案治疗非小细胞肺癌的临床研究

目的　比较MNP和MVP方案治疗晚期非小细胞肺癌 (NSCLC)的疗效和不良反应。方法　 12 6例晚期NSCLC患者随机分为A和B组 ,A组采用MNP(丝裂霉素 去甲长春花碱 顺铂 )方案化疗。B组采用MVP(丝裂霉素 长春酰胺 顺铂 )方案化疗。至少连用 2个周期后评价疗效。结果　A组有效率为 5 4.0 % ( 3 4/63 ) ,B组有效率为 3 4.9% ( 2 2 /63 ) ,无显著性差异 (P>0 .0 5 ) ;其中对腺癌有效率A组为 44 .4% ( 16/3 6) ,B组为 3 3 .3 % ( 12 /3 6)。A组静脉炎发生率为 2 8.6% ( 14 /4 9) ,B组为 0 (P <0 .0 5 ) ,其它不良反应 2组无显著性差异。结论　MNP方案为治疗晚期NSCLC较为有效和安全的化疗方案     

参麦注射液对阿霉素所致大鼠心肌损伤保护作用的实验研究

目的　观察参麦注射液 (SMI)对阿霉素 (ADM )诱导大鼠心肌损伤的保护作用和抗氧化作用。方法　选用ADM诱导大鼠心肌损伤模型。SD大鼠 60只 ,随机分为 3个组 ,每组 2 0只 ,分别为正常组、治疗组、对照组。正常组 :实验第 1～ 9天注射生理盐水 ,每天 3ml/kg ,1次 /天。治疗组 :实验第 1～ 9天注射参麦注射液 ,每天 3ml/kg ,1次 /天 ,第 4天注射阿霉素 ,隔天 1次 ,连用 3次 ,用生理盐水配置成 1mg/ml,每次 3mg/kg。对照组实验 1～ 9天注射生理盐水 ,每天 3ml/kg ,1次 /天。第 4天注射阿霉素 ,以后隔天 1次 ,连用 3次 ,用生理盐水配置成 1mg/ml,每次 3mg/kg。到期测定血丙二醛 (MDA )含量和超氧化物歧化酶(SOD )活性 ,并进行心肌病理检查。结果　对照组MDA水平明显高于治疗组 ,对照组SOD水平则显著低于治疗组 ,即加用SMI可提高SOD活性 ,降低MDA含量。SMI能明显减轻大鼠心肌损伤 ,对照组与治疗组比较 ,治疗组心肌损伤明显减轻 ,治疗组与正常组比较无显著性差异。参麦注射液有抗氧化作用 ,与对照组比较 ,血SOD水平升高 ,MDA水平降低 ,心肌病理计分下降。结论参麦注射液有抗氧化作用和对阿霉素所引起的心脏毒性具有保护作用 ,为临床寻找有效的阿霉素所致心肌损伤保护药物提供良好的客观依据 ,值得临床推广应用     

Denosumab in patients with cancer and skeletal metastases: A systematic review and meta-analysis

Background

We conducted a systematic review of the literature to determine the efficacy and safety of denosumab in reducing skeletal-related events (SRE) in patients with bone metastases.

Methods

A literature search using MEDLINE, EMBASE, Web of Science and The Cochrane Collaboration Library identified relevant controlled clinical trials up-to-March 14, 2012. Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. The primary outcomes of interest were SRE, time to first on-study SRE, and overall survival. Secondary outcomes included pain, quality of life, bone turnover markers (BTM), and adverse events.

Results

Six controlled trials including 6142 patients were analyzed. Compared to zoledronic acid, denosumab had lower incidence of SRE with a risk ratio (RR) of 0.84 (95% confidence intervals (CI) 0.80–0.88), delayed the onset of first on-study SRE (RR 0.83; 95% CI 0.75–0.90) and time to worsening of pain (RR 0.84; 95% CI 0.77–0.91). No difference was observed in overall survival with pooled hazard ratio of 0.98 (95% CI 0.90–1.0). For total adverse events, denosumab was similar to zoledronic acid (RR 0.97; 95% CI 0.89–1.0). No significant differences were observed in the frequency of osteonecrosis of the jaw (RR 1.4; 95% CI 0.92–2.1). Patients on denosumab had a greater risk of developing hypocalcemia (RR 1.9; 95% CI 1.6–2.3).

Conclusions

Denosumab was more effective than zoledronic acid in reducing the incidence of SRE, and delayed the time to SRE. No differences were found between denosumab and zoledronic acid in reducing overall mortality, or in the frequency of overall adverse events.     

蛋白激酶C的下调与KBV200细胞多药耐药性的关系

目的　探讨蛋白激酶C (PKC)在肿瘤多药耐药 (MDR)中的作用。方法　3 2 P掺入法测定PKC的活性 ;Westernblot法检测KBV2 0 0细胞株PKC亚型的表达和亚细胞分布 ;实验组用十字孢碱 (SP)预孵育KBV2 0 0细胞 ;MTT法检测耐药株KBV2 0 0细胞的耐药性。结果　SP可下调膜组分和浆组分的PKC活性及总活性 ;使PKCα膜组分和浆组分的表达均降低 ,PKCβ的膜组分消失 ,浆组分PKCβ的表达稍增强 ,PKCε的膜组分和浆组分表达无变化 ;SP可降低VCR、ADR对KBV2 0 0细胞的IC50 值 (P <0 0 1)。结论　SP使KBV2 0 0细胞耐药性降低 ,可能与下调PKC有关。     

High Dose Hydroxyurea in Collection of Philadelphia Chromosome-Negative Stem Cells in Chronic Myeloid Leukaemia

High dose hydroxyurea (HU) was used in a pilot study to assess its efficacy in mobilizing Philadelphia (Ph) chromosome negative progenitor cells in chronic myeloid leukaemia (CML). Five patients received 12g/M² oral HU in divided doses. Side effects were minimal, allowing outpatient administration. Nine to fourteen days later 4 patients achieved a mean leukocyte nadir of 3.5 × 10⁹/L (Range 2.4-4.9) and a mean platelet nadir of 99 × 10⁹/L (Range 95-108). Peripheral blood mononuclear cells (PB-MNC) sampled prior to the HU priming were 100% Ph positive. Between 10 and 18 days post HU, 3 patients achieved a marked reduction (80-100%) in the number of Ph positive metaphases in PB-MNC collected by apheresis. One patient failed to achieve any Ph suppression. Polymerase chain reaction analysis (PCR) for the bcr-abl fusion product remained positive in all samples.

Rapid rises in CFU-GM numbers were associated with a return to 100% Ph positive metaphases however slower rises represented recovery with predominantly Ph negative cells, allowing apheresis collection of these cells.

We conclude that HU induces a reproducible leukocyte nadir with sufficient stem cell mobilization for potential autologous transplantation. Higher doses of HU together with early and intensive apheresis is required to maximize Ph negative progenitor cell harvests.     

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence

Background: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. Case presentation: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Discussion: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. Conclusion: In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.     

NP与MNP方案治疗NSCLC近期疗效及毒性的对比分析

目的 :对比观察二药和三药联合化疗方案治疗非小细胞肺癌 (NSCLC)的近期疗效和毒性反应。方法 :6 2例初治的Ⅲb～Ⅳ期NSCLC ,随机分成A组 (去甲长春新碱 2 5mg/m2 静注第 1、8天 +顺铂 80mg/m2 静滴 ,分 2天 ,即NP方案 )、B组 (丝裂霉素 6mg/m2 静注第 1天 +去甲长春新碱 2 5mg/m2 静注第 1、8天 +顺铂 80mg/m2 静滴 ,分 2天 ,即MNP方案 )两组 ,分别化疗 2周期 ,每 4周为一周期。结果 :A组有效率为 33 3%、B组有效率为 37 9% (P >0 0 5 ) ;血小板降低A组为33 3% ,B组为 5 8 6 % (P <0 0 5 )。两组其余毒性反应无显著差异。结论 :二药联合可能比三药联合毒性低 ,而有效率无显著差异。     

Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis

The aim of this study was to determine the efficacy of palliative oxygen for relief of dyspnoea in cancer patients. MEDLINE and EMBASE were searched for randomised controlled trials, comparing oxygen and medical air in cancer patients not qualifying for home oxygen therapy. Abstracts were reviewed and studies were selected using Cochrane methodology. The included studies provided oxygen at rest or during a 6-min walk. The primary outcome was dyspnoea. Standardised mean differences (SMDs) were used to combine scores. Five studies were identified; one was excluded from meta-analysis due to data presentation. Individual patient data were obtained from the authors of the three of the four remaining studies (one each from England, Australia, and the United States). A total of 134 patients were included in the meta-analysis. Oxygen failed to improve dyspnoea in mildly- or non-hypoxaemic cancer patients (SMD=-0.09, 95% confidence interval -0.22 to 0.04; P=0.16). Results were stable to a sensitivity analysis, excluding studies requiring the use of imputed quantities. In this small meta-analysis, oxygen did not provide symptomatic benefit for cancer patients with refractory dyspnoea, who would not normally qualify for home oxygen therapy. Further study of the use of oxygen in this population is warranted given its widespread use.     

两种不同方案治疗晚期非小细胞肺癌的疗效比较(英文)

Objective: The aim of this study was to analyze and compare the recent efficacy and toxicity of a three-drug platinum-based regimen (A regimen): [cisplatin (DDP) + gemcitabine (GEM) + vinorelbine (NVB)] and a two-drug combination without a platinum drug (B regimen): GEM + NVB, which were used to treat 55 advanced non-small cell lung cancer (NSCLC) patients, in a bid to provide a guidance for clinical treatment. Methods: Twenty-four cases of advanced NSCLC (stage III-IV) patients were treated with A regimen ...     

Ⅰ期非小细胞肺癌的分子预后

目的联合检测Ⅰ期非小细胞肺癌（NSCLC）的细胞增殖,凋亡和血管生成,探讨Ⅰ期非小细胞肺癌预后分层。方法应用免疫组织化学方法检测118例Ⅰ期非小细胞肺癌,30例肺良性组织和30例正常肺组织血管内皮生长因子（VEGF）的表达,应用Ki67标记检测细胞增殖指数（PI）。TUNEL法检测70例Ⅰ期非小细胞肺癌,30例正常肺组织凋亡指数（AI）。结果单因素分析结果表明,肿瘤血管浸润、VEGF高表达、高PI、低AI为Ⅰ期非小细胞肺癌的不良预后因素。多因素分析结果显示,肿瘤血管浸润（BVI）、VEGF及PI可以作为影响Ⅰ期非小细胞肺癌预后的独立因素。根据免疫组化综合评分（IRS）IRS=VEGF＋PI＋AI,将患者分为低危组及高危组,5年总体生存率分别为82.22%,23.33%,有显著性差异（P=0.0056）。综合评分可作为独立预后因素（RR=4.878,95%CI：1.379～17.258,P=0.014）。结论联合检测肿瘤的细胞增殖,凋亡和血管生成,可能实现对Ⅰ期非小细胞肺癌的预后分层,判断预后以及指导治疗。     

Interaction between gemcitabine and mitomycin-C in vitro

Both gemcitabine (2′,2′-difluorodeoxycytidine; dFdCyd) and mitomycin-C (MMC) are active against several solid malignancies. dFdCyd is an attractive agent for use in combination with drugs which damage DNA and with radiation therapy because of its ability to inhibit DNA replication and repair as well as its radiosensitizing effect. We hypothesized that the repair of MMC adducts in DNA might be inhibited by dFdCyd leading to a synergistic effect. To test this possibility, we studied the effect of combining dFdCyd and MMC in HT29 human colon carcinoma cells in vitro. The cells were exposed to a variety of drug concentration ratios and schedules, then assessed for clonogenic survival. D₅₀ values (drug concentration at which clonogenicity is inhibited by 50%) were calculated, and the interactive effects of the two drugs were evaluated using median effect analysis. In this approach, if the calculated combination index (CI) is <1, 1, or >1, it indicates synergism, additivity, or antagonism, respectively (Chou and Talalay 1984). We found that marked synergy (CI of 0.5–0.7) was produced by concurrent exposure to mitomycin and gemcitabine. In contrast, sequential treatment led only to additivity. These findings suggest that, when combined in an appropriate schedule, the chemosensitizing effect of gemcitabine may be beneficial in the treatment of malignancies which are sensitive to MMC. Received: 19 November 1998 / Accepted: 21 June 1999     

Proficiency of DNA repair genes and microsatellite instability in operated colorectal cancer patients with clinical suspicion of lynch syndrome

Background

Lynch syndrome (LS) diagnosis is underestimated, and most of the patients remain undetected after colorectal resections. The study aims to assess the frequency of LS in patients undergoing surgical treatment for colorectal cancer (CRC).

Methods

A total of 458 CRC patients were operated from January 2005 to December 2008. Positive CRC family history (FH) was present in 118 (25.8%) patients. Histologic sections were reviewed for microsatellite instability (MSI) criteria (Bethesda guidelines), immunohistochemical (IHC) analysis for MLH1, MSH2, MSH6, PMS2 proteins, through the avidin-biotin-peroxidase complex, MSI (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) and BRAF somatic mutation.

Results

Of the 118 patients with FH, 61 (51.69%) met at least one of the revised Bethesda criteria. IHC was abnormal in 8 (13.1%) and MSI in 12 patients (20%). BRAF was negative in all cases. MSI histopathological included: intratumoral lymphocytes (47.5%), expansive tumors (29.5%) mucinous component (27.8%) and Crohn’s like reaction in (14.7%). There was an association between the revised Bethesda criteria with: sex, mucinous histology and Crohn’s like reaction; MSI and IHC with PMS2 and MLH1. Revised Bethesda criteria 4 had 10.6 increased chances to display positive MSI. We have proposed a score to contribute as a practical tool in the diagnosis of LS.

Conclusions

The frequence of LS in resected CRC patients was 2.6%. The criterion 4 Revised Bethesda was associated more strongly with the presence of MSI.     

替莫唑胺与洛莫司汀治疗脑胶质瘤的临床观察

目的 比较替莫唑胺（TMZ）与洛莫司汀（CCNU）治疗脑胶质瘤的疗效、生存期及不良反应。方法 64例首次术后脑胶质瘤患者随机分为TMZ组和CCNU组各32例,两组患者先给予常规放疗,2Gy/d,5d/W,共持续4～6W,射线总剂量50～60Gy。放疗结束后1周开始化疗。TMZ组口服TMZ（0.015～0.02）mg/(cm2·d),5d/W,每5天为1个疗程,每疗程间隔23天,28天为1个治疗周期,根据患者耐受情况给药3～5个周期。CCNU组口服CCNU(0.005～0.006)mg/(cm2·d),5d/W,疗程和治疗周期同TMZ组。结果 TMZ组疗效明显优于CCNU组（U=1.9675,P=0.0245）;TMZ组平均生存期（14.5±2.5）月,明显高于CCNU组（10.5±1.5）月（t=7.7611,P=0.000）;TMZ组恶心、呕吐、乏力的发生率明显低于CCNU组（χ2=4.0635,P=0.0437）;TMZ组骨髓抑制程度明显低于CCNU组（U=3.2314,P=0.0006）。结论 TMZ比CCNU更明显地缩小肿瘤体积,延长患者的生存期,副作用少,提高患者的生活质量,值得临床推广应用。     

鼻咽癌患者放射性骨坏死引起的正电子显像假阳性结果1例及文献复习

目的:探讨鼻咽癌(NPC)患者放射性骨坏死(osteoradionecrosis,ORN)引起正电子假阳性结果的原因及避免因此引发诊断错误的方法。方法:回顾性分析1例放疗后的鼻咽癌患者,行鼻咽部MRI及正电子显像后,再行组织病理学检查,对三种结果进行分析、比较。结果:MRI及正电子显像均诊断患者颅底区域肿瘤复发,组织病理学结果则显示鼻咽部病灶为放射性骨坏死。因此正电子扫描结果为假阳性结果。结论:鼻咽癌患者放疗后所致的放射性骨坏死容易引起正电子显像假阳性结果并可能引发不必要的治疗,因此NPC患者的正电子图像,对于可能的局限性肿瘤复发诊断,应该非常慎重。     

The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma

IntroductionCholangiocellular carcinoma (CCA) is an aggressive malignancy with a dismal prognosis. Among curative treatment options for CCA, radical surgical resection with extrahepatic bile duct resection, hepatectomy and en-bloc lymphadenectomy are considered the mainstay of curative therapy. Here, we aimed to identify prognostic markers of clinical outcome in CCA-patients who underwent surgical resection in curative intent.Material and methodsBetween 2011 and 2016, 162 patients with CCA (perihilar CCA (pCCA): n = 91, intrahepatic CCA (iCCA): n = 71) underwent surgery in curative intent at our institution. Preoperative characteristics, perioperative data and oncological follow-up were obtained from a prospectively managed institutional database. The associations of overall- (OS) and disease-free-survival (DFS) with clinico-pathological characteristics were assessed using univariate and multivariable cox regression analyses.ResultsThe median OS and DFS were 38 and 36 months for pCCA and 25 and 13 months for iCCA, respectively. Lymphovascular invasion (LVI) and lymph node metastasis as well as surgical complications as assessed by the comprehensive complication index (CCI) and tumor grading were independently associated with OS for the pCCA (LVI; RR = 2.36, p = 0.028; CCI; RR = 1.04, p < 0.001) and iCCA cohorts (N-category; RR = 3.21, p = 0.040; tumor grading; RR = 3.75, p = 0.013; CCI, RR = 4.49, p = 0.010), respectively. No other clinical variable including R0-status and Bismuth classification was associated with OS.ConclusionMajor liver resections for CCA are feasible and safe in experienced high-volume centers. Lymph node metastasis and LVI are associated with adverse clinical outcome, supporting the role of systematic lymphadenectomy. The assessment of LVI may be useful in identifying high-risk patients for adjuvant treatment strategies.     

2-Fluorine-18-fluoro-2-deoxy-D glucose positron emission tomography in the pretreatment staging of Hodgkin's disease: Influence on patient management in a single institution

Purpose:Optimum therapy for patients with Hodgkin's disease (HD)is determined by a number of prognostic factors, one of which is an accuratedefinition of extent of disease (stage). Computerised tomography is widelyused in staging but cannot reliably evaluate normal sized lymph nodes and someextranodal sites, e.g., liver, spleen and bone marrow.2-Fluorine-18-fluoro-2-deoxy-D glucose (FDG) has been shown to concentratepreferentially in lymphoma sites (whether in nodal or extranodal tissue) andtherefore may have a useful role in staging patients with HD. This studycompares concurrent computerized tomography (CT) and FDG positron emissiontomography (PET) in the staging of Hodgkin's disease and assesses thefrequency of stage migration and possible changes in therapy related to theuse of PET scanning. Patients and methods:This was a single centre retrospective studyof 44 patients with Hodgkin's disease who underwent both staging CT and PETprior to treatment between September 1993 and August 1998 at St. Thomas'Hospital. The number and sites of disease were assessed for each patient,documenting any stage and therapy modification prompted by PET findings. Results:One hundred fifty-nine sites of disease were demonstratedin forty-four patients by FDG–PET compared with eighty-four by CT. Asa result, 18 (40.9%) patients were upstaged, nine of these byFDG-uptake in splenic or extranodal sites not visualised on CT. Only threepatients were downstaged by PET results. Eleven patients (25%) hadtreatment modified by PET scan findings. Conclusions:Significantly more sites of disease were identifiedby PET than CT resulting in stage changes and a modification of therapy in25% of patients. This has important implications not only for currentpatient management but also for the design of future clinical trials.     

HMVP与MVP方案治疗晚期非小细胞肺癌的临床研究

目的 :旨在观察羟基喜树碱 (hydroxycamptothecin ,HCPT)联合丝裂霉素 (mitomycin ,MMC)、长春花碱酰胺 (vindesine ,VDS)和顺铂 (cisplatin ,DDP)组成的HMVP和MVP方案治疗晚期NSCLC的近期、远期疗效和毒副反应。方法 :将 90例晚期NSCLC患者随机分为HMVP组 (4 6例 )与MVP组 (4 4例 ) ,观察两组的近期及远期疗效、毒副反应和生存情况。结果 :HMVP和MVP有效率分别为 39.5 4 %和 35 .5 7% ,两组之间无显著性差异 (P >0 .0 5 ) ;两组的中位缓解期、中位生存期、一年及二年生存率亦无明显差异。两组的Ⅲ～Ⅳ度白细胞抑制率、Ⅲ～Ⅳ度血小板抑制率、Ⅲ～Ⅳ度恶心 /呕吐发生率、Ⅲ～Ⅳ度便秘发生率之间均无显著性差异 (P >0 .0 5 )。结论 :MVP方案治疗晚期NSCLC的疗效略低于HMVP方案 ,但后者未显示出明显的疗效优势 ,却可能增加白细胞抑制、恶心 /呕吐和便秘的发生率 ,也增加了患者的经济负担 ;故在NSCLC化疗中宜选择MVP方案     

Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis

Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine), which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC) with tetrahydrouridine (H4U). We propose that CldC, coadministered with H4U, is metabolized in the following manner: CldC----CldCMP----CldUMP---- ----CldUTP----DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U. Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 microM) or FdC (0.02 microM) + H4U (0.1 mM) followed 6 hr later by CldC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 +/- 4% to 15 +/- 1% (+/- S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CldC + H4U alone (at these concentrations) results in 20% substitution of CldU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (4%). In this approach we seek to obtain preferential conversion of CldC to CldUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.     

Comprehensive bioinformatics analysis of functional molecules in colorectal cancer

BackgroundColorectal cancer (CRC) is the 3rd most common cancer and the 2nd leading cause of cancer-related death. Numerous studies have found that aberrations in cellular molecules play an important role in the development of tumors. Studying and determining the interactions between these molecules can contribute to the diagnosis, treatment, and prognosis of tumors.MethodsThe {"type":"entrez-geo","attrs":{"text":"GSE151021","term_id":"151021"}}GSE151021, {"type":"entrez-geo","attrs":{"text":"GSE156720","term_id":"156720"}}GSE156720, and {"type":"entrez-geo","attrs":{"text":"GSE156719","term_id":"156719"}}GSE156719 data sets were analyzed to screen the differentially expressed messenger RNAs (DEmRNAs), long non-coding RNAs (DElncRNAs), and microRNAs (DEmiRNAs) in CRC. Database for Annotation, Visualization and Integrated Discovery (DAVID) and the Search Tool for the Retrieval of Interacting Genes/Proteins software were used to examine gene enrichment and the hub genes. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN was used to verify the expression of the hub genes. To analyze the overall survival (OS) of the hub genes, Kaplan-Meier plotter (KM plotter) was performed. Finally, the miRCancer database, TargetScan, and {"type":"entrez-geo","attrs":{"text":"GSE156719","term_id":"156719"}}GSE156719 were used to identify the targets of the identified miRNAs. To predict the lncRNA-miRNA interactions, we used DIANA-LncBase v2 and {"type":"entrez-geo","attrs":{"text":"GSE156720","term_id":"156720"}}GSE156720. Finally, the visualization protein‑protein interaction (PPI), competitive endogenous RNA (ceRNA) network was constructed using Cytoscape v3.1.ResultsBy analyzing {"type":"entrez-geo","attrs":{"text":"GSE151021","term_id":"151021"}}GSE151021 and {"type":"entrez-geo","attrs":{"text":"GSE156720","term_id":"156720"}}GSE156720, 23 upregulated mRNAs and 10 downregulated mRNAs were identified as sharing the differentially expressed genes (DEGs) between CRC and adjacent tissues. Furthermore, nucleolar protein 14 (NOP14), the sonic hedgehog (SHH) signaling molecule, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), the BCL2 apoptosis regulator (BCL2), and zinc finger E-box binding homeobox 2 (ZEB2) were considered hub genes. The constructed lncRNA-miRNA-mRNA network revealed 7 intersecting miRNAs (4 upregulated and 3 downregulated), 79 lncRNAs (40 upregulated and 39 downregulated), and 5 mRNAs (3 upregulated and 2 downregulated). Finally, we determined that the dysregulation of lncRNAs, such as HCG16, CASC9, SNHG16, HAND2-AS1, and NR2F1-AS1, secluded altered the expression of several miRNAs, such as hsa-miR-193a-5p, hsa-miR-485-5p, hsa-miR-17-5p, and hsa-miR-92a-3p, and affected the occurrence and development of CRC.ConclusionsWe identified a series of DElncRNAs, DEmRNAs, and DEmiRNAs in CRC that might be considered potential biomarkers in understanding the complex molecular pathways leading to CRC development.