Clinical pharmacokinetics of oxaliplatin and 5-fluorouracil administered in combination with leucovorin in Korean patients with advanced colorectal cancer

Purpose: Oxaliplatin and 5-fluorouracil (5-FU) act synergistically in colorectal cancer. Here, we evaluated the pharmacokinetics of oxaliplatin and 5-FU administered in combination with leucovorin in Korean advanced colorectal cancer patients. Methods: Nine patients with advanced colorectal cancer were included in this study. The 3-week regimen consisted of oxaliplatin (2-h infusion, 130 mg/m² on day 1) followed by 5-FU and leucovorin (2-h infusion, 425 and 20 mg/m², respectively, from day 1 to day 5). Blood samples were taken and platinum concentrations in total plasma, plasma ultrafiltrate, and RBCs were determined. Plasma concentrations of 5-FU were also determined. Results: The C _max of oxaliplatin was observed at the end of infusion, with mean values of 4.66, 0.84, and 2.69 μg/ml for total plasma, plasma ultrafiltrate, and RBC samples, respectively. C _max ratios of total/free were significantly higher than those reported in other ethnic groups. An accumulation of platinum was observed in RBCs, but not in total plasma and plasma ultrafiltrate samples. A significant correlation was found between the total body clearance of ultrafiltrable platinum and creatinine clearance. The C _max of plasma 5-FU ranged from 23.9 to 533.8 ng/ml, indicating large inter-patient pharmacokinetic variations. Conclusions: This study shows that pharmacokinetics of oxaliplatin in Korean patients is comparable with that of other ethic groups, except for the higher C _max ratios of total/free. The C _max of 5-FU in plasma showed large variations among patients. Antitumor efficacy in Korean advanced colorectal cancer patients given oxaliplatin and 5-FU should be further evaluated with respect to pharmacokinetic variabilities.     

rAd-p53 enhances the sensitivity of human gastric cancer cells to chemotherapy

AIM:To investigate potential antitumor effects of rAd-p53 by determining if it enhanced sensitivity of gastric cancer cells to chemotherapy.METHODS:Three gastric cancer cell lines with distinct levels of differentiation were treated with various doses of rAd-p53 alone,oxaliplatin(OXA) alone,or a combination of both.Cell growth was assessed with an 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide assay and the expression levels of p53,Bax and Bcl-2 were determined by immunohistochemistry.The pre...     

Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells

The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vitro and in vivo is clearly enhanced by hyperthermia. We investigated whether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminomethylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-1,2-diaminocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisplatin was used for comparison. SW 1573 cells were incubated with cisplatin, lobaplatin or oxaliplatin at different concentrations for 1 h at 37°, 41° and 43°C. The reproductive capacity of cells was determined by cloning experiments. Immunocytochemical detection of platinum-DNA adducts was performed with the rabbit antiserum NKI-A59. At 37°C, cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotoxicity of cisplatin, lobaplatin and oxaliplatin. There was no further increase in cytotoxicity at 43°C compared to 41°C for cisplatin and oxaliplatin. A further increase in cytotoxicity at 43°C was observed for lobaplatin. At 43°C thermal enhancement was higher for lobaplatin than for oxaliplatin, with the reverse pattern at 41°C. For both drugs, thermal enhancement of cytotoxicity was lower than observed for cisplatin. Immunocytochemical detection of platinum-DNA adducts was feasible for all the drugs. Adduct formation was enhanced at 43°C for cisplatin, lobaplatin and oxaliplatin with a relative increase of 410%, 170% and 180%. These results seem to confirm that an increase in platinum-DNA adduct formation is involved in the in vitro thermal enhancement of cytotoxicity. The observed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin in vitro warrants further in vivo investigations.Abbreviation TER thermal enhancement ratio     

Thermotherapy enhances oxaliplatin-induced cytotoxicity in human colon carcinoma cells

AIM: To observe the synergistic effects of hyperthermia in oxaliplatin-induced cytotoxicity in human colon adenocarcinoma Lovo cells.METHODS: The human colon adenocarcinoma cell line Lovo was obtained from Sun Yat-Sen University. Cells were sealed with parafilm and placed in a circulating water bath, and was maintained within 0.01  °C of the desired temperature (37  °C, 39  °C, 41  °C, 43  °C and 45  °C). Thermal therapy was given alone to the negative control group while oxaliplatin was administered to the treatment group at doses of 12.5 μg/mL and 50 μg/mL. Identification of morphological changes, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and Western blotting were used to investigate the effect of thermochemotherapy on human colon adenocarcinoma Lovo cells, including changes in the signal pathway related to apoptosis.RESULTS: A temperature-dependent inhibition of cell growth was observed after oxaliplatin exposure, while a synergistic interaction was detected preferentially with sequential combination. Thermochemotherapy changed the morphology of Lovo cells, increased the inhibition rate of the Lovo cells (P < 0.05) and enhanced cellular population in the G₀/G₁ phase (16.7% ± 4.8 % in phase S plus 3.7% ± 2.4 % in phase G₂/M, P < 0.05). Thermochemotherapy increased apoptosis through upregulating p53, Bax and downregulating Bcl-2. Protein levels were elevated in p53, Bax/Bcl-2 in thermochemotherapy group as compared with the control group (P < 0.05).CONCLUSION: Thermochemotherapy may play an important role in apoptosis via the activation of p53, Bax and the repression of Bcl-2 in Lovo cells.     

Efficacy of docetaxel combined with oxaliplatin and fluorouracil against stage III/IV gastric cancer

AIM: To investigate the clinical efficacy and toxic effects of neoadjuvant chemotherapy using docetaxel combined with oxaliplatin and fluorouracil for treating stage III/IV gastric cancer.METHODS: A total of 53 stage III/IV gastric cancer patients were enrolled into the study and treated with neoadjuvant chemotherapy. Two of the cases were excluded. The program was as follows: 75 mg/m² docetaxel and 85 mg/m² oxaliplatin on day 1 and 1500 mg/m² fluorouracil on days 1 to 3 for three weeks.RESULTS: The tumour changes, postoperative remission rate, changes in the symptoms and adverse reactions were observed. The overall clinical efficacy (complete remission + partial remission) of the neoadjuvant chemotherapy was 62.7%. R0 radical resection was performed on 60.8% of the patients, with a remission rate (pathological complete response + pathological subtotal response + pathological partial response) of 74.2%. The Karnofksy score improved in 42 cases. The toxicity reactions mostly included myelosuppression, followed by gastrointestinal mucosal lesions, nausea, vomiting and diarrhoea.CONCLUSION: Neoadjuvant chemotherapy consisting of docetaxel combined with oxaliplatin and fluorouracil is effective for stage III/IV gastric cancer. However, the treatment is associated with a high incidence of bone marrow suppression, which should be managed clinically.     

Methods of overcoming treatment resistance in colorectal cancer

Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy.     

不同新辅助化疗方案治疗进展期胃癌的临床研究

目的：比较ECF和FOLFOX新辅助化疗方案治疗进展期胃癌的疗效与毒副作用。方法：用ECF、FOLFOX化疗方案治疗进展期胃癌62例，3周为1个周期。所有患者完成3-4个周期新辅助化疗后评价疗效。ECF方案为表柔比星50mg／m2，第1天；亚叶酸钙（LV）200mg／m^2，第1—3天；5-氟尿嘧啶（5-Fu）600mg／m^2，第1—3天；顺铂20m异／m^2，第1-3天。FOLFOX方案为奥沙利铂100mg／m^2，静脉滴注2h，第1天；LV200mg／m^2，静脉滴注2h后推注5．Fu400mg／m^2，后续5-Fu1g／m^2。化疗泵持续48—72h恒速静脉输入，第1-2天。结果：ECF组的总有效率为37％（11／30），其中临床完全缓解（CR）3％（1例），部分缓解（PR）33％（10例），疾病稳定（SD）40％（12例）．疾病进展（PD）23％（7例），6例（20％）肿瘤TNM分期降低。FOLFOX组的总有效率为47％（15／32），其中CR3％（1例）．PR44％（14例）。SD34％（11例），PD19％（6例），10例（31％）TNM分期降低。两组白细胞下降、胃肠道反应相似：ECF组脱发程度较重，FOLFOX组外周感觉神经异常明显。结论：两组新辅助化疗方案对进展期胃癌均有效，毒性反应均可耐受。FOLFOX组疗效高于ECF组。     

原发性肝癌患者的疗效和安全性研究简

目的探究吉西他滨（GEM）联合奥沙利铂（OXA）治疗晚期原发性肝癌患者的疗效与安全性。方法将2010年1月至2013年10月收治的60例晚期原发性肝癌患者,按照随机数字表法,分为观察组与对照组,每组均30例,分别采用吉西他滨联合奥沙利铂治疗与单纯采用吉西他滨治疗,对比两组患者的,l告床疗效与安全性。结果经各自治疗后,观察组的局部控制率为63．33％,显著高于对照组的33．33％,差异具有显著性（X2=4．271,P=0．039）;血小板与中性粒细胞减少是两组患者的主要毒副作用,且在不同的毒副作用发生率对比,差异无统计学意义（P〉0．05）。结论吉西他滨联合奥沙利铂治疗晚期原发性肝癌患者,能够有效改善临床疗效,提高局部控制率,且不增加发生毒副作用的风险,值得临床推广应用。     

奥沙利铂不同静脉输注途径的不良反应对比分析

目的：比较奥沙利铂经3种不同静脉途径输注致毒副反应发生率及程度,探讨其最适宜的输注方式。方法选择奥沙利铂为主化疗的胃肠道肿瘤患者90例,采用随机数余数分组法分为3组,每组30例,分别通过外周静脉、深静脉穿刺置入中心静脉导管（ CVC）及经外周静脉穿刺中心静脉置管（ PICC）输注奥沙利铂,比较不同静脉途径输注患者周围神经、血液系统、消化系统毒副反应的发生率及程度。结果外周静脉组、CVC组、PICC组患者周围神经炎发生率分别为37．50％,21．43％,10．00％,差异有统计学意义（χ2＝6．628,P＜0．05）;血液系统毒副反应发生率分别为53．13％,53．57％,50．00％,消化系统毒副反应分别为78．13％,92,86％,73．33％,差异均无统计学意义（χ2值分别为0．090,3．892;P＞0．05）。结论奥沙利铂静脉输入首选PICC,其次CVC,避免使用外周静脉输注。     

含奥沙利铂与含顺铂方案肝动脉栓塞化疗治疗中晚期肝癌的疗效

目的分析含奥沙利铂（L—OHP）与含顺铂（DDP）方案行肝动脉化疗栓塞术（TACE）对中晚期原发性肝癌（HCC）的治疗效果和不良反应。方法将108例中晚期HCC患者随机分成2组。治疗组55例,行含L—OHP方案介入治疗,L—OHP 130mg／m^2,替加氟（FT207）500～750mg／m^2,用葡萄糖溶液稀释后分别注入血管,根据肿瘤病灶的大小以多柔比星（ADM）40mg／m^2＋超液化碘油10～30ml乳化后进行血管栓塞。对照组53例,行含DDP方案介入治疗,DDP40mg／m^2,FT207500～750mg／m^2,用葡萄糖溶液稀释后分别注入血管,根据肿瘤病灶的大小以ADM40mg／m^2＋超液化碘油10～30ml乳化后进行血管栓塞,并予水化利尿。结果治疗组近期有效率为67.3％（37／55）,与对照组[47．2％（25／53）]比较,差异有统计学意义（P〈0．05）。治疗组甲胎蛋白（AFP）下降率为73．1％（31／43）,与对照组[44．7％（17／38）]比较,差异有统计学意义（P〈0．05）。主要不良反应为消化道反应,治疗组恶心、呕吐发生率较对照组低,差异有统计学意义（P〈0．05）。两组骨髓抑制、肝功能受损、末梢神经炎发生率差异无统计学意义。两组均未见心、肾损害。结论采用以L—OHP为主的方案行TACE治疗中晚期肝癌疗效肯定,安全性好,患者耐受好。