异环磷酰胺联合奈达铂治疗复发性卵巢上皮癌56例的疗效观察

目的：观察异环磷酰胺联合奈达铂治疗复发性卵巢上皮癌的近期疗效。方法选择56例复发性卵巢上皮癌患者,均采用异环磷酰胺和奈达铂的联合化疗方案（其中d1-3异环磷酰胺1.2/m2,d1奈达铂90mg/m2）每21d为1疗程,每2个疗程评价疗效。结果56例复发性卵巢上皮癌患者经该方案治疗后,其中完全缓解16例,部分缓解27例,进展8例,稳定5例,总有效率76.8%,不良反应主要为骨髓抑制、胃肠道反应等,无因化疗毒性而死亡病例。结论异环磷酰胺联合奈达铂治疗复发性卵巢上皮癌有效,毒副反应可以耐受。     

紫杉醇联合顺铂、5-氟尿嘧啶治疗晚期食管癌近期疗效观察

目的 观察紫杉醇联合顺铂(DDP)加亚叶酸钙(CF)和5-氟尿嘧啶(5-FU)方案治疗晚期食管癌的近期疗效及安全性.方法 观察55例晚期食管癌患者,PTX 135～175 mg·m-2,静脉滴注3 h,d1,DDP 20 mg·m-2 d1～d4、CF 0.2g·m-2 d2～d3、5-FU 2.0g·m-2持续静滴4...     

多西他塞合用顺铂的Ⅰ期临床药动学研究

目的:研究多西他塞(泰索帝)在与顺铂联合用药情况下的药动学特征,确定和推荐Ⅱ期临床试验的给药方案.方法:选择晚期转移ⅢB或Ⅳ期非小细胞肺癌(NSCLC)患者15例,分成4组,分别按25,30,35,40mg·m-2剂量,每周1次方案给药,在每28d中的d1,8,15静注给药,4个剂量组均按75mg·m-2固定剂量给予顺铂.在第1周期的d1和d15给药前即刻,静注30min给药结束印刻,给药结束后10,30,45,60,90min及3,5,8,12,24h分别采血,用LC MS/MS测定血药浓度.用WinNonlin软件按恒速静脉输注给药的三室模型进行分析并计算相关药动学参数.经对数转换的药动学参数包括剂量归一化的AUCN,CmaxN和Cl,用SAS Proc混合程序进行检验.结果:在给药d1,当剂量从25增加到40mg·m-2时,平均AUC值从(1 393±288)增加到(1 968±757)μg·h·L-1;d15平均AUC值从(1 423±149)增加到(1 751±564)μg·h·L-1.在给药d1和d15,CmaxN,AUCN及Cl值均无显著性差异.结论:多西他塞静脉给药后Cmax和AUC值与剂量成比例增加,而Cl值与剂量水平无关,其药动学不受合用顺铂的影响.     

顺铂不同剂量联合长春瑞滨治疗非小细胞肺癌的临床研究

目的:对比研究顺铂(DDP)不同剂量联合长春瑞滨(NVB)在非小细胞肺癌(NSCLC)患者化疗中的疗效和不良反应。方法:123例Ⅲ～Ⅳ期NSCLC患者,采用不同剂量DDP联合长春瑞滨进行分组对照研究,分为低剂量DDP组(n=67)与高剂量DDP组(n=56)。低剂量DDP组给予NVB25mg.m-2,静脉滴注,第1、8天;DDP20mg.m-2,静脉滴注,第1～5天。高剂量DDP组给予NVB25mg.m-2,静脉滴注,第1、8天;DDP60mg.m-2,静脉滴注,第1～2天。21d为一周期。化疗2周期后评定疗效。结果:高剂量DDP组与低剂量DDP组的有效率分别为41.1%、28.4%(P>0.05);高剂量DDP组白细胞减少总发生率为87.5%,明显高于低剂量DDP组的71.6%(P<0.05);2组Ⅲ～Ⅳ度白细胞减少发生率无显著性差异(P>0.05)。结论:DDP高剂量组与低剂量组的临床疗效相当。高剂量顺铂组毒性反应的发生率显著高于低剂量组,但严重毒性反应的发生率相近。     

顺铂加吉西他滨与顺铂加长春瑞滨一线治疗晚期非小细胞肺癌的对照研究

目的:探讨顺铂(DDP)加吉西他滨(GEM)与顺铂加长春瑞滨(NVB)治疗晚期非小细胞肺癌(NSCLC)的疗效、不良反应。方法:66例NSCLC患者分别接受GEM/DDP方案与NVB/DDP方案化疗GEM/DDP(GP)化疗方案:GEM1000mg.m-2d1、8DDP75mg.m-2,总剂量分为3d使用,dl~3NVB/DDP(NP)化疗方案:NVB25mg.m-2d1、8;DDP80mg.m-2,总剂量分为3d使用,d1~3。21d为一周期,所有病例均接受2个周期以上的治疗。观察两组的近期有效率、中位生存时间(MST)、1年生存率、不良反应。结果:GP和NP方案的有效率分别为41.6%和36.7%,中位生存期分别为10.3个月和9.6个月,1年生存率分别为44.4%和40.0%(P=0.33)。GP组的III~IV级血小板减少47.2%,显著高于NP组6.6%(P<0.01),而NP组的中性粒细胞减少高于GP组,分别为60%和33.3%(P<0.05)。结论:GP和NP方案治疗晚期NSCLC疗效相当,但毒性反应略有差别。     

长春瑞滨联合顺铂治疗中晚期乳腺癌的临床观察

目的:观察长春瑞滨(盖诺)联合顺铂方案治疗中晚期乳腺癌的临床疗效.方法:运用盖诺(25 mg·m-2IVD d1,d8)加顺铂(DDP 80 mg·m-2IV d1)治疗中晚期乳腺癌36例.结果:总有效率达66.7%.主要不良反应为骨髓抑制,胃肠道反应和静脉炎.白细胞减少的发生率100%,其中Ⅲ～Ⅳ度达55.6%;恶心、呕吐的发生率92.3%,Ⅲ～Ⅳ度达11.1%;静脉炎的发生率11.1%.结论:国产长春瑞滨联合顺铂对中晚期乳腺癌疗效确切,且毒性可以耐受,可以作为对蒽环类药物治疗后复发,中晚期乳腺癌患者的第二线治疗方案.     

PCF和OLF两种联合化疗方案一线治疗晚期胃癌疗效及安全性研究

目的比较PCF方案与OLF方案治疗晚期胃癌疗效及不良反应。方法 56例晚期胃癌患者随机分为PCF方案组(28例)和OLF方案组(28例)。PCF方案:紫杉醇135 mg·m-2,d1;顺铂20 mg·m-2,d1~4;5-FU 500 mg·m-2,d1~5。OLF方案:奥沙利铂135 mg·m-2,d1;亚叶酸钙200 mg·m-2,d1~5;5-FU 500 mg·m-2,d1~5。两组均21 d为一周期,2个周期后评判近期疗效及安全性。结果 PCF方案组ORR 42.86%、DCR 75%;OLF方案组ORR 53.57%、DCR 82.14%;两组近期疗效无明显差异(P>0.05)。Ⅲ°、Ⅳ°恶心、呕吐反应发生率PCF方案与OLF方案相比差异无显著性(25.0%vs 21.4%,P>0.05);Ⅲ°、Ⅳ°白细胞减少发生率PCF方案明显高于OLF方案(35.7%vs 14.3%,P<0.05);而神经毒性反应,则OLF方案高于PCF方案(21.4%vs 0,P<0.05)。结论 PCF方案与OLF方案一线治疗晚期胃癌疗效相当,缓解率均较高。不良反应方面,各有特点,均可耐受。     

老年晚期非小细胞肺癌DP方案化疗的疗效分析

目的评价国产多西他赛(多帕菲)联合顺铂(DDP)方案(简称DP方案)在治疗老年人晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)中的近期疗效、不良反应的多因素分析。方法对病理证实的78例晚期NSCLC患者,采用DP方案化疗,多帕菲30mg/m2。第1、8d给药,DDP 20mg/m2第1～4d给药,21d为1周期。至少化疗2周期后复查评价疗效。结果本组研究总有效率35.90%,其中Ⅲ期总有效率41.03%,Ⅳ期有效率20.00%。不良反应Ⅲ、Ⅳ度粒细胞减少发生率20.51%.Ⅲ、Ⅳ度血小板减少发生率5.13%,恶心、呕吐的Ⅲ、Ⅳ度发生率为17.95%。结论多帕菲联合DDP方案治疗老年性非小细胞肺癌疗效高且不良反应低,是治疗老年性NSCLC较好的方案,值得进一步推广。     

顺铂用于非小细胞肺癌化疗的药动学

目的:比较不同顺铂给药方案治疗非小细胞肺癌的顺铂血药浓度及药动学参数变化.方法:16名非小细胞肺癌化疗患者使用顺铂联合长春瑞滨方案治疗,静脉滴注给药,根据顺铂用药方案不同分为高剂量组与低剂量组.高剂量组用药方案:第1,2天顺铂60 mg·m-2,第1,8天长春瑞滨25 mg·m-2低剂量组用药方案:第1～5天顺铂20 mg·m-2,第1,8天长春瑞滨25 mg·m-2.动态采集患者给药前及末次给药后96 h内血样本,高效液相色谱法测定给药后顺铂血药浓度,3P97软件计算药动学参数.结果:从0～96 h,高剂量组血药浓度显著高于低剂量组(P<0.05),但差异随时间延长逐渐缩小.除AUC外,两组间其他药动学参数差异无显著性,但个体间变异大,变异系教为12.7%～99%.结论:结论AUC值对于顺铂个体化方案设计具有重要参考价值.     

多西他赛联合吡柔比星与顺铂2种方案治疗晚期乳腺癌的临床疗效观察

目的:比较多西他赛联合吡柔比星(TT)与顺铂(TP)2种方案治疗晚期乳腺癌的临床疗效和不良反应。方法:TT组采用吡柔比星40～50 mg.m-2,静脉注射,d1;多西他赛75 mg.m-2,静脉滴注1 h,d2。TP组采用多西他赛75 mg.m-2,静脉滴注1h,d1;顺铂75～80 mg.m-2(分2～3 d),静脉滴注,d2～3或d4;2组使用多西他赛前30 min分别静脉注射地塞米松10 mg和西咪替丁300 mg,并于10 h后开始口服地塞米松8 mg,每日2次,连服3 d;化疗前30 min静脉滴注托烷司琼5～6 mg。以上每3～4周为1个周期,至少完成2个周期。结果:69例患者共接受190个周期的化疗,每例至少完成2个周期,均可评价疗效。2组总有效率(RR)为50.7%(35/69);TT方案组RR为52.8%(19/36),CR为13.9%(5/36);TP方案组RR为48.5%(16/33),CR为6.1%(2/33),2组近期疗效比较差异无统计学意义,P>0.05。TT组脱发发生率为100%(36/36),高于TP组的54.5%(18/33),2组比较差异有统计学意义,P<0.05;而骨髓抑制、恶心、呕吐和腹泻及Ⅲ+Ⅳ度毒性反应,2组比较差异均无统计学意义,P>0.05。结论:TT和TP方案治疗晚期乳腺癌患者,疗效相近,RR较高,不良反应可以耐受。     

The delivery of platinum drugs from thermosensitive hydrogels containing different ratios of chitosan

New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were prepared and evaluated for use in the delivery of the platinum drugs, cisplatin and carboplatin. The effects of polymers containing different ratios of chitosan on the physicochemical and drug release characteristics were examined. The sol-gel transition temperature of the hydrogels was determined by differential scanning calorimetry (DSC) and viscometry. Discrepancies in the transition temperature among the various polymer systems were more pronounced when determined by viscosity compared by DSC, with the CPN showing a higher transition temperature than PNIPAAm. The cross-sectional structure and surface topography of the hydrogels were examined by scanning electronic microscopy (SEM) and atomic force microscopy (AFM), respectively. The incorporation of chitosan further increased the entanglement of the hydrogel network. An increase in the chitosan ratio in the polymers (CPN-H) also increased the cross-linking structure. A smoother surface of hydrogel matrices was observed for CPN compared with PNIPAAm. All hydrogels tested significantly reduced drug release compared with an aqueous solution. The release rate of platinum drugs from PNIPAAm was retarded at the late stage. CPN matrices could continuously deliver platinum drugs during the experiment. The rate of release from CPN-H was generally slower than that from hydrogels and had a lower chitosan ratio (CPN-L), presumably due to the more-tortuous pathways in the hydrogels. Thermosensitive hydrogels like those prepared in this study may be a promising carrier for the delivery of platinum drugs, as the drug release can be controlled and sustained using CPN networks.     

Interactions of platinum complexes containing cationic, bicyclic, nonplanar piperidinopiperidine ligands with biological nucleophiles

The determination of the structures and DNA interactions and the reactions with GSH and ubiquitin of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl, where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA), were performed. X-ray structures and NMR studies of the NH3 and MA complexes showed that both pip rings were in the chair conformation and that the second pip ring is fluxional. The DNA binding studies showed that these complexes bind to calf thymus DNA nearly an order of magnitude more quickly than cisplatin and form covalent adducts that stabilize the double helix. The binding of the pip-pip complexes to DNA results in high unwinding angles (approximately 30 degrees) and in the formation of approximately 25% interstrand cross-links. The pip-pip complexes reacted with GSH more quickly than cisplatin and transplatin, and the rate of reaction decreased with increasing steric bulk of the ligand trans to the pip-pip. The reactions with ubiquitin resulted in monofunctional binding to Met1. Only the NH3, MA, and DMA complexes reacted with ubiquitin in a slower and less efficient fashion than cisplatin.     

Adenine-N3 in the DNA minor groove - an emerging target for platinum containing anticancer pharmacophores

The minor-groove is an important receptor for enzymes and proteins involved in the processing and expression of genomic DNA. Small molecules capable of interfering with these processes by virtue of their ability to form adducts within the recognition sequences targeted by these enzymes/proteins have potential applications as cytotoxic and gene-regulating agents. Until recently, the targeting of the minor groove by platinum-based agents has been a widely unexplored opportunity. As part of this focused review on irreversible minor-groove modifying agents acting on adenine-N3, we summarize work performed in our laboratory and by our collaborators on a novel platinum-acridine conjugate, PT-ACRAMTU ([PtCl(en)(ACRAMTU)](NO(3))(2), en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, acridinium cation). The design of this agent as a non-cisplatin type pharmacophore has led to a groundbreaking discovery, the unprecedented intercalator-driven formation of platinum-adenine-N3 adducts in the minor groove of DNA. The minor-groove reactivity of PT-ACRAMTU represents a new paradigm in platinum-DNA interactions, which opens new avenues in the design of platinum-based therapeutics acting by a mechanism different from that of agents currently in clinical use.     

Review of dose-intense platinum and/or paclitaxel containing chemotherapy in advanced and recurrent epithelial ovarian cancer

Ovarian cancer is the most lethal gynecological cancer in women in the western world with a 5-year survival of 49.7%. Advanced stage ovarian cancer is treated both surgically and with chemotherapy, but despite initial high response rates of 60- 75%, many women experience disease recurrence with a dismal prognosis, 5 year overall survival for FIGO stage IIIc and IV disease being only 32 and 18%. In an attempt to improve outcome for both primary and recurrent disease, dose-intense and dose-dense chemotherapy regimens have been investigated. This overview summarizes these results in first and second-line treatment. In first-line treatment, no benefit was found of dose-intense regimes in the majority of the studies, only toxicity was increased. However, results are conflicting with the recent Japanese Gynecologic Oncology Group (JGOG) trial showing an improved progression free and overall survival in patients treated with dose-dense weekly paclitaxel combined with standard 3-weekly carboplatin. For recurrent disease dose-dense weekly combination chemotherapy seems to be very effective in patients with platinum-resistant ovarian cancer. Several phase II studies showed an increase in response rate, progression free survival and overall survival for dose-dense paclitaxel and carboplatin, compared to results of nonplatinum chemotherapy. In platinum-sensitive ovarian cancer, on contrary, the results of weekly paclitaxel and carboplatin seem to be comparable with standard 3-weekly regimens.     

New platinum(II) complexes containing both an O,O'-chelated acetylacetonate ligand and a sulfur ligand in the platinum coordination sphere induce apoptosis in HeLa cervical carcinoma cells

We report the cytotoxic effects obtained in HeLa cells of three newly synthesized platinum complexes containing both an O,O'-chelated acetylacetonate ligand and a sulfur ligand in the platinum coordination sphere, which show, by (1)H NMR, negligible reactivity with purine bases. These compounds induce cell death with [Pt(O,O'-acac)(gamma-acac)(DMS)] being the most effective (IC(50)=0.98+/-0.056 and 1.82+/-0.023 microM for [Pt(O,O'-acac)(gamma-acac)(DMS)] and cisplatin, respectively). About 50% of cells died after 5h treatment with 100 microM [Pt(O,O'-acac)(gamma-acac)(DMS)] whilst a 16 h incubation was required to get the same results using 100 microM cisplatin. Cellular accumulation measurements, after treatment with equimolar drug concentrations, indicated the major lipophilicity and cellular uptake of the new compounds. While the cytotoxicity of cisplatin was due to both intracellular accumulation and DNA binding, that of [Pt(O,O'-acac)(gamma-acac)(DMS)] was associated with intracellular Pt accumulation only, since it has low reactivity to DNA in intact cells and in vitro. The reaction of the new complexes with guanosine and 5'-GMP was negligible, whereas the L-methionine instantly reacted with the initial Pt complexes. Both cisplatin and [Pt(O,O'-acac)(gamma-acac)(DMS)] induced apoptosis in HeLa cells. [Pt(O,O'-acac)(gamma-acac)(DMS)] provoked the early signs of apoptosis induction (cleavage of PARP and activation of caspases-9, -3 and -7) only 1h after addition of the drug. However, in cisplatin-treated cells, cleavage of PARP was seen after 9h with activation of caspases also proceeding more slowly. In conclusion, these results indicate that the newly synthesized platinum(II) complexes have high and rapid cytotoxic activity in vitro, and suggest that DNA may not be their primary target.     

奥沙利铂原料药的含量测定

目的建立奥沙利铂原料药的含量测定方法。方法采用炽灼残渣法测定奥沙利铂原料药含量,并将结果与HPLC法进行比较。结果2种方法均具可行性。结论炽灼残渣法操作简便,结果准确。     

Photoactivatable platinum complexes

The development of photoactivatable prodrugs of platinum-based antitumor agents is aimed at increasing the selectivity and hence lowering toxicity of this important class of antitumor drugs. These drugs could find use in treating localized tumors accessible to laser-based fiber-optic devices. Pt(IV) complexes appeared attractive because these octahedral complexes are usually substitution inert and require reduction to the Pt(II) species to become cytotoxic. Based on the knowledge of Pt(IV) photochemistry, Pt(IV) analogs of cisplatin, [Pt(en)Cl(2)] and transplatin were designed, synthesized and investigated for their ability to be photoreduced to cytotoxic Pt(II) species. Two classes of photoactivatable Pt complexes have been looked at thus far: diiodo-Pt(IV) and diazido-Pt(IV) diam(m)ine complexes. The first generation, diiodo-Pt(IV) complexes, represented by cis, trans-[Pt(en)(I)(2)(OAc)(2)], react to visible light by binding irreversibly to DNA and forming adducts with 5'-GMP in the same manner as [Pt(en)Cl(2)]. Furthermore, the photolysis products are cytotoxic to human cancer cells in vitro. However, these complexes are too reactive towards biological thiols (i.e., glutathione), which rapidly reduced them to cytotoxic Pt(II) species, thus making them unsuitable as drugs. The second generation, diazido-Pt(IV) complexes, represented by cis, trans, cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] and cis, trans-[Pt(en)(N(3))(2)(OH)(2)], are also photosensitive, binding irreversibly to DNA and forming similar products with DNA and 5'-GMP in the presence of light as the respective Pt(II) complexes. However, they are stable to glutathione and thus show very low dark cytotoxicity. Light of lambda(irr) = 366 nm activates both complexes to cytotoxic species that effectively kill cancer cells by destroying their nuclei, leaving behind shrunken cell ghosts. Interestingly, the all-trans analog, trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] is non-toxic to HaCaT keratinocytes in the dark, but as active as cisplatin in the light. These studies show that photoactivatable Pt(IV) antitumor agents represent a promising area for new drug development.     

Toxicity of platinum compounds

Since the introduction of platinum-based combination chemotherapy, particularly cisplatin, the outcome of the treatment of many solid tumours has changed. The leading platinum compounds in cancer chemotherapy are cisplatin, carboplatin and oxaliplatin. They share some structural similarities; however, there are marked differences between them in therapeutic use, pharmacokinetics and adverse effects profiles [1-4]. Compared to cisplatin, carboplatin has inferior efficacy in germ-cell tumour, head and neck cancer and bladder and oesophageal carcinoma, whereas both drugs seem to have comparable efficacy in advanced non-small cell and small cell lung cancer as well as ovarian cancer [5-7]. Oxaliplatin belongs to the group of diaminocyclohexane platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid [8,9]. Other platinum compounds such as oral JM216, ZD0473, BBR3464 and SPI-77, which is a pegylated liposomal formulation of cisplatin, are still under investigation [10-13], whereas nedaplatin has been approved in Japan for the treatment of non-small cell lung cancer and other solid tumours. This review focuses on cisplatin, carboplatin and oxaliplatin.     

卡培他滨联合铂类对比氟尿嘧啶联合铂类治疗晚期胃癌的Meta分析

摘 要 目的:评价卡培他滨联合奥沙利铂或顺铂与氟尿嘧啶联合奥沙利铂或顺铂治疗晚期胃癌的有效性和安全性。方法：采用计算机检索Cochrane Library、PubMed、Embase、中国期刊全文数据库（CNKI）、维普中文科技期刊全文数据库（VIP）、万方数据库,对符合纳入标准的随机对照试验(RCT)进行质量评价,并采用RevMan5.2软件进行Meta分析。结果：共纳入22项RCT,合计1 601例患者。卡培他滨化疗组在总有效率[RR=1.28,95%CI（1.15,1.42）,P＜0.001]、完全缓解率[RR=1.58,95%CI（1.09,2.30）,P=0.02]、部分缓解率[RR=1.23,95%CI（1.09,1.39）,P＜0.001]和疾病控制率[RR=1.12,95%CI（1.06,1.20）,P＜0.001]方面均优于氟尿嘧啶化疗组。安全性方面,卡培他滨化疗组手足综合征的发生率高于氟尿嘧啶化疗组,而恶心呕吐、口腔黏膜炎和白细胞减少的发生率较低。对于腹泻、神经毒性、肝脏毒性、贫血和血小板减少等不良反应的发生率两组差异无统计学意义（P＞0.05）。结论：与氟尿嘧啶联合铂类相比,卡培他滨联合铂类治疗晚期胃癌的疗效更高,安全性更好。由于纳入研究的质量不高,该结论尚需高质量、多中心和大样本的RCT进一步证实。