奥沙利铂抗肿瘤作用的研究

观察奥沙利铂抗肿瘤作用。方法采用药物学体内实验法及体外人癌细胞培养药杀伤法,观察了奥沙利铂抑瘤活性并与顺铂相比较。结果奥沙利铂（９ｍｇ／ｋｇ－２．２５ｍｇ／ｋｇ,腹腔注射,３次）用药的３组小鼠,在体内接种Ｌ１２１０后,观察３０天均无腹水出现,全部存活,达到治愈水平。在相同剂量下（９ｍｇ／ｋｇ－２．２５ｍｇ／ｋｇ,腹注射,３次）败类沙利铂的毒性明显低于顺铂,每剂量组小鼠体重增加都高于顺铂组。结论体外     

奥沙利铂抗肿瘤作用及其免疫学新机制的研究进展

奥沙利铂是第3代的铂类抗肿瘤药,具有高效、低毒和不易耐药等特点,明显地不同于第1代和第2代的铂类药物。新近的研究表明,奥沙利铂除了细胞毒作用,即直接作用于肿瘤细胞DNA外,其抗肿瘤作用的重要新机制是影响机体免疫学功能。本文拟对奥沙利铂的抗肿瘤作用的免疫学机制的研究进展进行简要综述和讨论,以帮助肿瘤医师熟悉有关学术动态,拓展临床治疗和研究思路。     

奥沙利铂联合HLF方案治疗晚期胃癌的临床研究

  目的 研究奥沙利铂（L-OHP）联合HLF[羟基喜树碱（HCPT）+ 5-氟尿嘧啶（5-Fu）／醛氢叶酸（LV）]方案治疗晚期胃癌的近期疗效及其安全性。方法 37例晚期胃癌患者均经病理学证实（男27例，女10例），以联合HLF方案予全身化疗，每4周为1周期，每例至少接受2～3周期（中位数5周期）化疗。按照WHO标准进行疗效评价。结果 37例中完全缓解（CR）1例（2.7 %），部分缓解（PR）13例（35.1 %），总有效（RR = CR+PR）率为37.8 %（14／37），Karnofsky提高20分以上者占45.9 %（17／37）。主要毒副反应为骨髓抑制和消化系统反应，恶心、呕吐发生率较高；神经毒性大多为Ⅰ~ Ⅱ度，对症处理后均能缓解。所有患者均未因严重不良反应中断或退出治疗，无化疗相关死亡病例。中位随访时间15.6个月，中位疾病进展时间（TTP） 6.2个月，中位生存期（OS） 9.2个月。结论 L-OHP联合HLF方案治疗晚期胃癌近期疗效肯定，毒副反应较轻。     

奥沙利铂联合替加氟和羟基喜树碱治疗晚期胃癌的研究

目的研究奥沙利铂联合替加氟和羟基喜树碱治疗进展及转移性胃癌的疗效和毒副反应。方法采用奥沙利铂130mg／m^2，静滴2小时，第一天；替加氟1．0，静滴2小时，第1—5天；羟基喜树碱10mg静滴2小时，第1—5天；21天或28天为1周期，行4周期治疗后判定疗效。结果其中完全有效3例(8．8％)，部分有效11例(32．4％)，无变化14例(41．2％)，进展6例(17．6％)，总有效率41.2％，中位生存期9个月。毒副反应以骨髓抑制，感觉性神经毒性为主，其中白细胞减少占44．1％，血小板减少占41．2％，感觉性神经毒性占82．4％，无化疗相关死亡。结论奥沙利铂联合替加氟和羟基喜树碱治疗晚期胃癌疗效肯定，毒副反应能耐受，值得进一步试用。     

奥沙利铂过敏反应临床特征的研究

  目的  通过分析结直肠癌患者使用含奥沙利铂方案化疗前常规行地塞米松5 mg预处理后过敏反应发生的临床特征,为降低奥沙利铂过敏风险提供参考依据。  方法  回顾性分析2014年1月至2017年10月苏州大学附属常州肿瘤医院收治的242例含奥沙利铂方案化疗的结直肠癌患者临床资料,统计过敏反应发生率,对多项因素与过敏反应关系进行单因素分析,采用Logistic多因素回归模型分析影响过敏反应发生的独立因素,并探讨奥沙利铂过敏患者再次使用奥沙利铂治疗的结局。  结果  242例结直肠癌患者使用含奥沙利铂方案化疗前行地塞米松5 mg静推,发生过敏反应12例（4.9%）,均为Ⅰ型过敏反应,中位发生时间6（5.5~ 10.5）个周期,中位累积剂量895（716.5~1 075.0）mg。多因素分析提示存在无奥沙利铂间隔期为过敏反应的独立预测因素（P= 0.04）。其中3例奥沙利铂过敏患者接受药物预处理后再次使用奥沙利铂,1例（33.3%）成功完成治疗。  结论  奥沙利铂使用前常规行小剂量地塞米松预处理,过敏反应发生率低于文献报道,安全性高,无奥沙利铂间隔期患者再次使用该药过敏反应发生率明显提高,奥沙利铂过敏患者再次使用需谨慎。      

小剂量奥沙利铂联合复方苦参注射液抗肿瘤血管生成的实验研究

目的:观察小剂量奥沙利铂(L-OHP)联合复方苦参注射液对小鼠皮下移植瘤生长的抑制作用以及对肿瘤组织中血管内皮生长因子(VEGF)的表达和微血管密度(MVD)的影响.方法:建立H22肝癌荷瘤小鼠模型后随机分为5组:5%葡萄糖注射液20ml/kg阴性对照组、环磷酰胺(CTX)20mg/kg阳性对照组、奥沙利铂0.75mg/kg组、复方苦参注射液3mL/kg组,复方苦参注射液3ml/kg+奥沙利铂0.75mg/kg联合组,每组10只.各组均给予腹腔等容量注射,连续用药10天.停药次日处死小鼠,计算瘤重抑制率.免疫组化法检测肿瘤组织中VEGF和MVD的表达.结果:小剂量奥沙利铂单药及联合复方苦参注射液组的瘤重均明显低于阴性对照组(P<0.05);肿瘤组织中的VEGF和MVD的表达明显低于阴性对照组(P<0.01).结论:小剂量奥沙利铂对H22肝癌细胞小鼠皮下移植瘤肿瘤组织具有明显抑制作用,联合复方苦参注射液具有明显相加抑制作用,能抑制肿瘤组织中VEGF和MVD的表达;小剂量奥沙利铂联合复方苦参注射液在体内可能具有抑制肿瘤组织血管生成的作用.     

奥沙利铂脱敏治疗及皮试的探索性研究

目的:探讨运用抗过敏药物预处理、奥沙利铂减慢速率输注或脱敏治疗进行奥沙利铂再化疗的可能性。尝试对奥沙利铂过敏的患者进行3个浓度梯度的皮试,同时分析奥沙利铂皮试结果与临床奥沙利铂过敏的符合率,了解皮试结果与临床奥沙利铂过敏的符合率。方法:对在本中心接受含奥沙利铂方案治疗的患者进行筛选,经临床医师根据临床症状和体征判断为奥沙利铂Ⅰ-Ⅲ度过敏反应的患者进入本研究。对Ⅰ-Ⅲ度奥沙利铂过敏的患者进行3个浓度梯度（0.01 mg/ml、0.1 mg/ml和5 mg/ml）的奥沙利铂皮试,并以5%葡萄糖水作为阴性对照。15~20分钟读取测试结果。如果皮疹最大径大于阴性对照3 mm判为阳性结果。之后根据奥沙利铂过敏反应的等级进行不同方式的干预措施。主要研究终点为奥沙利铂再次化疗3周期的完成率,次要终点为奥沙利铂皮试结果与临床医师判断之间的符合率。结果:2016年6月至2017年4月126例在本中心接受含奥沙利铂方案治疗的患者中,14例（11.1%）发生奥沙利铂过敏。发生奥沙利铂过敏反应的中位疗程数为第8疗程,过敏反应时患者已接受的奥沙利铂中位累积剂量为1 200 mg(600~1 500 mg),男性8例,女性6例,中位年龄51岁（43~73岁）。Ⅰ、Ⅱ度过敏反应10例,Ⅲ度过敏反应4例,无Ⅳ度过敏反应的患者。14例患者的皮试结果为:13例阳性。皮试结果与临床的符合率为92.9%。除1例Ⅲ度过敏反应的患者拒绝继续接受奥沙利铂治疗,其余13例均接受了奥沙利铂的再化疗。总体再化疗成功率为100%。 结论:本研究证实了本中心设计的奥沙利铂过敏的干预措施是可行的。奥沙利铂皮试与临床医师判断之间的符合率高。     

新型顺铂纳米微球的制备及性质研究

目的：采用自行合成的高分子载体,制备负载顺铂的纳米微球,全面考察其性质。方法：通过开环聚合法,制备单甲氧基聚乙二醇-聚己内酯（mPEG—PCL）两嵌段聚合物以及末端带有羟基的PCL作为载体,采用优化的w／o／w双乳化扩散／挥发法,制备负载顺铂的纳米微球。考察载体的结构、分子量、纳米微球的形态、粒径分布、稳定性、生物相容性等性质。结果：通过开环聚合法合成mPEG-PCL两嵌段聚合物以及末端带有羟基的PCL,测定分子量和设计分子量相近。通过双乳剂法制备的空白粒子平均粒径为326．9±5．4nm,载药粒子在冻干前后的粒径分别为339．1±4．9及370．3±2．5nm。粒子呈规整的球形,在水溶液中稳定。顺铂的载药效率为77．4％,载药量为4．72％。体外释放实验显示,载药粒子具有缓释特征,在6h、24h、48h分别释放53％、75％、93％。载体在高浓度时对细胞生长无抑制作用,毒性低。结论：研究表明这种新型载药系统具有良好的应用价值。     

新型顺铂纳米微球的制备及性质研究

目的:采用自行合成的高分子载体,制备负载顺铂的纳米微球,全面考察其性质.方法:通过开环聚合法,制备单甲氧基聚乙二醇-聚己内酯(mPEG-PCL)两嵌段聚合物以及末端带有羟基的PCL作为载体, 采用优化的w/o/w双乳化扩散/挥发法,制备负载顺铂的纳米微球.考察载体的结构、分子量、纳米微球的形态、粒径分布、稳定性、生物相容性等性质.结果:通过开环聚合法合成mPEG-PCL两嵌段聚合物以及末端带有羟基的PCL,测定分子量和设计分子量相近.通过双乳剂法制备的空白粒子平均粒径为326.9±5.4nm,载药粒子在冻干前后的粒径分别为339.1±4.9及370.3±2.5nm.粒子呈规整的球形,在水溶液中稳定.顺铂的载药效率为77.4%,载药量为4.72%.体外释放实验显示,载药粒子具有缓释特征,在6h、24h、48h分别释放53%、75%、93%.载体在高浓度时对细胞生长无抑制作用,毒性低.结论:研究表明这种新型载药系统具有良好的应用价值.     

新型多西紫杉醇载药纳米微球的制备及其评价

目的:采用自行合成的高分子载体,制备负载多西紫杉醇(DOC)的纳米微球,全面评价其性质。方法:通过开环聚合法,制备单甲氧基聚乙二醇-聚己内酯(mPEG-PCL)两嵌段聚合物载体,考察载体的结构、相对分子质量、纳米微球粒径、形貌、生物相容性等性质。以改良的丙酮-纳米沉淀法制备负载DOC的载药纳米微球,以CCK-8法,评价该载药微球在体外对于肝癌细胞株H22的抗肿瘤活性,并与泰素帝相比较。结果:通过开环聚合法合成mPEG-PCL两嵌段聚合物,测定相对分子质量和设计相对分子质量相近。DOC纳米微球为不规则的圆形,表面光滑,其粒径<100nm。载体在高浓度时对细胞生长无抑制作用,毒性低。DOC的载药效率为81.3%,载药量为18.7%。体外细胞毒性显示,DOC纳米载体组IC50略小于裸药泰素帝。结论:该实验制备并评估了DOC载药纳米微球,为进一步研究提供了实验依据。     

Genistein靶向多肽偶联物的制备及体外抑瘤活性研究

目的:制备Genistein靶向多肽偶联物(GEN-P),增强Genistein的抑瘤活性。方法:采用固相法设计、合成能够与组织因子(TF)特异性结合的配体分子-FHS001,凝血酶原时间(PT)法测定其凝血活性,荧光显微镜直接检测其与高表达TF的人乳腺癌细胞株MCF-7的结合。通过异型双功能交联剂Sul-fo-SANPAH将FHS001与Genistein交联,制备偶联物GEN-P;MTT法检测其对MCF-7的杀伤作用。结果:合成的FHS001多肽能够与高表达TF的MCF-7细胞特异性结合且无明显的凝血活性。GEN-P偶联物在0.2～200.0μmol/L的浓度范围内对MCF-7细胞均有不同程度的增殖抑制作用,作用6h后抑制率为16.3%～83.1%,且呈一定的剂量依赖性。GEN-P和Genistein对MCF-7细胞的IC50分别为2.0和120μmol/L,GEN-P效果明显优于游离药物Genistein。结论:与FHS001偶联后Genistein的抑瘤活性明显增强,有希望进一步应用于癌症的治疗。     

Cost-effectiveness analysis of oxaliplatin compared with 5-fluorouracil/leucovorin in adjuvant treatment of stage III colon cancer in the US

BACKGROUND: The MOSAIC trial demonstrated that oxaliplatin/5-fluorouracil/leucovorin (FU/LV) (FOLFOX4) as adjuvant treatment of TNM stage II and III colon cancer significantly improves disease-free survival compared with 5-FU/LV alone. For stage III patients the 4-year disease-free survival (DFS) was 69% in the FOLFOX4 arm vs 61% in the LV5FU2 arm, P = .002). The cost-effectiveness of FOLFOX4 in stage III patients was evaluated from a US Medicare perspective. METHODS: By using individual patient-level data from the MOSAIC trial (median follow-up: 44.2 months), DFS and overall survival (OS) were estimated up to 4 years from randomization. DFS was extrapolated from 4 to 5 years by fitting a Weibull model and subsequent survival was estimated from life tables. OS beyond 4 years was predicted from the extrapolated DFS estimates and observed survival after recurrence. Costs were calculated from trial data and external estimates of resources to manage recurrence. RESULTS: Patients on FOLFOX4 were predicted to gain 2.00 (95% confidence interval [CI]: 0.63, 3.37) years of DFS over those on 5-FU/LV. The predicted life expectancy of stage III patients on FOLFOX4 and 5-FU/LV was 17.61 and 16.26 years, respectively. Mean total lifetime disease-related costs were $56,300 with oxaliplatin and $39,300 with 5-FU/LV. Compared with 5-FU/LV, FOLFOX4 was estimated to cost $20,600 per life-year gained and $22,800 per quality-adjusted life-year (QALY) gained, discounting costs and outcomes at 3% per annum. CONCLUSIONS: FOLFOX4 is likely to be cost-effective compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer. The incremental cost-effectiveness ratio compares favorably with other funded interventions in oncology.     

Hemolysis and thrombocytopenia following oxaliplatin administration

Oxaliplatin is a platinum derivative with an overall excellent safety profile that has a major role in the treatment of colorectal cancer. With a proven role now in the adjuvant setting, rare but potentially life‐threatening toxicities become a more significant issue. We report here a case of significant postinfusion hemolysis and thrombocytopenia in a patient undergoing adjuvant chemotherapy for stage III colon cancer, and review the literature. Six cases of hemolysis following oxaliplatin treatment have previously been reported, all in the setting of advanced colorectal cancer, with one case resulting in death. In three of the seven reports (including the present case), warning signs of low grade hemolysis were apparent during preceding cycles, with fever and/or back pain during the infusion being the most common feature. Our case appears to be the first reported with a direct antiglobulin test‐negative hemolysis with thrombocytopenia, with each of the previous reports postulating an autoimmune basis. Hemolysis and/or thrombocytopenia are potentially life‐threatening complications of oxaliplatin chemotherapy. With the increasing use of oxaliplatin in the adjuvant setting, clinicians need to be aware of this entity and the possible clinical warning signs that may be evident in preceding cycles.     

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery

Context: Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy.Objective: We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible.Patients and methods: From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (>5 cm), multinodular (>4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team.Results: In 151 patients, the size of liver metastases decreased by >50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19–28 months), with 28% surviving at five years (20%–35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25–71), with a five-year survival rate of 50% (38–61).Conclusion: This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.     

草酸铂的过敏反应

草酸铂属于第3代铂类化合物,是治疗结直肠癌的重要化疗药物。随着临床应用日渐广泛,对其过敏反应的认识逐渐加深。过敏类型主要包括I型和Ⅱ型过敏反应,特点不一。过敏源尚不确切。抗组胺药物和糖皮质激素可以缓解过敏症状,但作为预处理的效果不肯定。程度较轻的I型过敏患者可考虑进行脱敏治疗。     

Electroclinical biomarkers of early peripheral neurotoxicity from oxaliplatin

Mc HUGH J.C., TRYFONOPOULOS D., FENNELLY D., CROWN J. & CONNOLLY S. (2012) European Journal of Cancer Care Electroclinical biomarkers of early peripheral neurotoxicity from oxaliplatin Peripheral neuropathy is the principal dose‐limiting side effect of chemotherapy with oxaliplatin. Early biomarkers of oxaliplatin‐related neuropathy (ON) are important for guiding management and as outcomes for neuroprotective trials. We compared a number of clinical and neurophysiological techniques to identify early features of ON. Median nerve motor excitability testing, nerve conduction studies, vibration perception threshold (VPT) and clinical assessments were carried out on 17 patients and 105 controls. Neuropathy was graded using the total neuropathy score and National Cancer Institute Common Toxicity Criteria scales. Oxaliplatin causes a length‐dependent sensory neuropathy. The most sensitive early marker of neuropathy was abnormal VPT in the foot followed by diminished sensory nerve action potential amplitudes. Median nerve excitability studies revealed no biologically significant effects of treatment on motor axons. VPT is an easily applicable and effective marker of neuropathy at low cumulative doses of oxaliplatin. Nerve excitability measures may be useful in predicting ON but motor studies do not reveal early cumulative changes following treatment with the drug.     

Exacerbation of oxaliplatin neurosensory toxicity following surgery.

Combination of chemotherapy and surgical resection of metastases is the most promising strategy to improve the fraction of long-term survivors and cured patients in metastatic colorectal cancer. We reproducibly observed evidence of exacerbation of the oxaliplatin-induced neurosensory toxicity following surgery. Total, protein-bound and intra-erythrocytic concentrations of oxaliplatin were measured, whenever possible, immediately prior to surgery and 4, 24 and 48 h following surgical resection. Among 12 patients, seven (58%) patients reported immediate post-operative aggravation of the pre-existing neurotoxicity. At the time of surgery, we detected high intra-erythrocytic platinum concentrations in all patients (median: 1365 micro g/l, range: 820-2968 micro g/l). While ultrafilterable oxaliplatin was not detectable prior to surgery, it could be detected immediately after surgery and during 48 h. These results suggest that patients heavily pretreated with oxaliplatin may experience aggravation of neurotoxicity after surgery, probably through a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. This clinical observation might be the consequence of peroperative hemolysis.     

谷胱甘肽预防奥沙利铂神经毒性的疗效观察

目的:评价谷胱甘肽对奥沙利铂神经毒性的防治疗效[1]。方法:87例奥沙利铂全身化疗的肿瘤患者随机分为2组,治疗组44例(男性36例,女性8例),年龄为22-75岁,平均年龄为48岁;对照组43例(男性35例,女性8例),年龄为19-70岁,平均年龄为45岁。治疗组奥沙利铂化疗前2天,使用谷胱甘肽1200mg加入5%GS 250ml,静滴,每日一次,至化疗结束后3-5天;对照组予以保肝对症治疗,不使用谷胱甘肽。结果:治疗组奥沙利铂神经毒性发生率11.36%(5/44),对照组为51.16%(22/43),治疗组与对照组比较,差异有统计学意义(P<0.05)。结论:谷胱甘肽对预防奥沙利铂的神经毒性有较好效果,值得临床推行。