肝癌^131I—抗AFP抗体—MMC“双弹头”免疫导向治疗的研究

目的 观察一种集化疗和内照射于一体的新型“双弹头”免疫导向治疗肝癌的效果。方法 以大鼠抗人甲胎蛋白（ＡＦＰ）单克隆抗体（抗ＡＦＰＭｃＡｂ）和马抗人ＡＦＰ多克隆抗体（抗ＡＦＰＡｂ）为载体，＾１３１碘（＾１３１Ｉ）或＾１２５碘（＾１２５Ｉ）和丝裂霉素（ＭＭＣ）为“双弹头”用改良氯胺Ｔ法制备＾１３１Ｉ－抗ＡＦＰＭｃＡｂ－ＭＭＣ（双弹头Ｉ）和＾１３１Ｉ（或＾１２５Ｉ）－抗ＡＦＰＡｂ－ＭＭＣ（双弹头Ⅱ）治疗     

双弹头组合单抗免疫导向治疗肝癌的实验研究

以肝癌单克隆抗体ＨＡｂ１８、ＨＡｂ２５为载体，以￣（１３１）Ｉ、阿霉素（ＡＤＭ）为“弹头”．应用间接交联方法及氯胺Ｔ法，制备出肝癌“双弹头组合单抗”免疫导向偶合物［￣（１３１）Ｉ－ＨＡｂ１８－ＡＤＭ］／［￣（１３１）Ｉ－ＨＡｂ２５－ＡＤＭ］，其标记率４９．８％，比放射性６．８８×１０４Ｂｑ／μｇ，免疫结合率４２．５％。细胞毒实验结果显示双弹头组合单抗偶合物杀伤力显著强于单弹头单抗体偶合物（Ｐ＜０．０５）。荷肝癌棵鼠导向治疗实验，１６８小时ＳＰＥＣＴ扫描清楚定位，瘤／肝比值３．７３５±０．１２０，治疗效果显著强于其它各组（Ｐ＜０．０５）。上述结果表明，“双弹头”集中了化疗与放疗优点，二者协同，明显提高了杀伤效应；组合单抗较好地消除了肿瘤异质性对导向治疗的影响。     

肝癌“双弹头”组合单抗导向治疗的实验研究

以肝癌单抗ＨＡｂ１８、ＨＡｂ２５为载体，以１３１Ⅰ、阿霉素（ＡＤＭ）为弹头，应用间接交联及氯胺Ｔ法，制备出肝癌＂双弹头＂组合单抗免疫导向结合物１３１Ⅰ－ＨＡｂ１８－ＡＤＭ／１３１Ⅰ－ＨＡｂ２５－ＡＤＭ，其标记率４９.８％，比放射性６.８８×１０４Ｂｑ／ｕｇ，免疫结合率４２.５％。细胞毒实验结果显示“双单头”组合单抗结合物杀伤力显著强于单弹头单抗体结合物（Ｐ＜０.０５）。荷瘤鼠导向治疗实验，１６８小时ＳＰＥＣＴ扫描定位清晰，瘤／肝比值３.７３５±０.１２０，治疗效果显著强于其它各组（Ｐ＜０.０５）。上述结果表明，“双弹头”集中了化疗与放疗的优点，二者协同，提高了杀伤效应；组合单抗较好消除了肿瘤异质性对导向治疗的影响。     

^131I—抗AFPMcAb—MMC“双弹头”免疫导向治疗原发性肝癌的临床观察

研制一种新型的集化疗和内照射治疗于一体的“双弹头”免疫导向治疗药物＾１３１Ｉ－抗ＡＦ－ＰＭｃＡｂ－ＭＭＣ，并初步观察其临床疗效。药物采用以大鼠抗人甲胎蛋白单克隆抗体为载体，丝裂霉素Ｃ和＾１３１Ｉ为双弹头，通过直接偶联和改良氯胺Ｔ法制备，静脉给药治疗１２例中晚期原发性肝癌，疗效与同期进行经动脉插管灌注或加栓塞的１４例对照组比较，导向组肿瘤缩小率、血清ＡＦＰ下降率及１年生存率分别为４５．５％、８３．３     

抗人AFP—R—LCA McAb放免显像裸鼠人肝癌的实验研究

放射性核素１３１Ｉ标记的抗人小扁豆凝集素结合型甲胎蛋白异质体单克隆抗体（ＡＦＰ－Ｒ－ＬＣＡＭｃＡｂ），注射入荷瘤裸鼠腹腔后，能选择性地在裸鼠人肝癌模型肿瘤区积聚，其放射性核素浓度是裸鼠肝脏的５．２倍；而１３１Ｉ标记的正常小鼠ＩｇＧ（ｍＩｇＧ）及游离１３１Ｉ却无瘤区积聚，且在荷瘤裸鼠体内呈均匀分布。１３１Ｉ－ＡＦＰ－Ｒ－ＬＣＡＭｃＡｂ组γ照像均显示出裸鼠人肝癌的阳性定位。结果表明：ＡＦＰ－Ｒ－ＬＣＡＭｃＡｂ对人肝癌细胞有较强的亲和力及特异性，有希望成为肝癌放免显像及治疗的理想载体     

^131I—抗AFP—MMC“双弹头”导向治疗原发性肝癌毒副反应观察

目的：研究“双弹头”导向治疗原发性肝癌毒副反应。方法：用１３１Ｉ－抗ＡＦＰ－ＭＭＣ“双弹头”导向治疗原发性肝癌２９例（５４例次），用自身对照设计（单组比较设计），全组１３１Ｉ－平均治疗剂量为６２．０９×１０７Ｂｑ，（２１．５３～１４９．１１）×１０７Ｂｑ。结果：治疗后外周血象无明显变化，心和肾功能正常，肝功能ＡＬＴ有７例轻度升高；甲状腺功能Ｔ３、Ｔ４值下降分别有３例和１例，过敏反应出现３例。结论：本组治疗耐受性良好，毒副反应轻微。     

肝癌“双弹头”免疫导向药物的实验研究

以肝细胞癌单克隆抗体ＨＡｂ１８为载体，应用间接交流方法及氯胺Ｔ法，将１３１Ｉ和抗癌药物阿霉素（ＡＤＭ）连接到ＨＡｂ１８上，制备出“双弹头”肝癌免疫导向药物１３１Ｉ─ＨＡｂ１８─ＡＤＭ，其标记率为８５％，比放射性为７．７３×ｌ０４Ｂｑ／μｇ（１．９８μＣｉ／μｇ），免疫结合率为４３．５％。细胞毒实验结果显示，１３１Ｉ─ＨＡｂ１８─ＡＤＭ对靶肿瘤细胞ＳＭＭＣ─７７２１的杀伤效果明显强于ＨＡｂ１８─ＡＤＭ、ＨＡｂ１８─１３１Ｉ、ＡＭＤ。１３１Ｉ─ＨＡｂ１８─ＡＤＭ具有选择性的高效杀伤作用，它集中了化疗与内放射治疗的优点，互相补充，展示了肿瘤导向治疗的光明前景。     

贞芪扶正冲剂在UFTM联合治疗晚期胃癌中减毒作用的初步临床观察

本文报告贞芪扶正冲剂在ＵＦＴＭ和ＵＦＴ治疗晚期胃癌６例中的减毒作用，治疗设Ａ组为ＵＦＴＭ加贞芪，Ｂ组ＵＦＴＭ，Ｃ组ＵＦＴ加贞芪。ＵＦＴ总量２３－４０ｇ，ＭＭＣ总量４８－６０ｍｇ，贞芪１５ｇ２／日共８周，观察结果毒副反应者Ｂ＞Ａ＞Ｃ（Ｐ＜０．０５），白细胞血小板降低在Ｉ及Ｉ以上Ｂ＞Ａ＞Ｃ（Ｐ＜０．０５），近期疗效Ａ＞Ｂ＞Ｃ）Ｐ＜０．０５）提示贞芪冲剂在联合化疗中有减毒作用，从而可提高疗效。     

血清AFP,CEA,SF检测对肝癌的诊断意义

作者检测４９例转移性肝癌、１０７例原发性肝癌和４６例健康人血清的ＡＦＰ、ＣＥＡ、ＳＦ。结果：转移性肝癌和原发性肝癌的ＡＦＰ阳性率为２．０％和４８．６％（Ｐ＜０．０１）、ＣＥＡ阳性率为８３．７％和２６．２％（Ｐ＜０．０１）、ＳＦ阳性率为７１．４％和７３．８％（Ｐ＞０．０５），原发癌为腺癌和非腺癌的转移性肝癌，其ＣＥＡ阳性率分别为９６．９％和５８．８％（Ｐ＜０．０１）。提示ＡＦＰ和ＣＥＡ对转移性肝癌有诊断意义，尤其对原发癌为腺癌的转移性肝癌，ＡＦＰ和ＳＦ有助于原发性肝癌的诊断。     

癌性渗出液中IL-2、IL-6、IL-8、TNFα·论著·和IFNγ活性分析

目的与方法应用ＥＬＩＳＡ法研究了１８例癌性渗出液（ＭＯＦ）中内源性ＩＬ－２、ＩＬ－６、ＩＬ－８、ＩＦＮγ和ＴＦＮα的生物学活性,并与恶性肿瘤病人（ＭＴＤ）血清、正常人、结核性胸膜炎（ＴＢＰ）和肝硬化病人（ＣＲＳ）进行了比较分析。结果ＭＴＤ血清中ＩＬ－６活性高于与正常成人组（Ｐ＜０．０５）;ＩＬ－２和ＩＦＮγ活性亦低下（Ｐ＜０．５）。ＭＴＤ血清中ＩＬ－２、ＩＬ－６ＴＮＦα活性显著低于ＴＢＰ（Ｐ＜０．００１）;ＩＬ－８和ＩＦＮγ活性亦降低（Ｐ＜０．０５）。ＭＯＦ中的ＩＬ－６、ＩＦＮγ水平显著高于ＴＢＰ组（Ｐ＜０．０１;Ｐ＜０．０５）;ＩＬ－２却明显降低（Ｐ＜０．０５）。ＭＴＤ血清中ＩＬ－２、ＩＬ－６低于ＣＲＳ组（Ｐ＜０．０５）;ＭＯＦ中ＩＬ－６、ＩＮＦγ水平高于ＣＨＡＤ组（Ｐ＜０．００１;Ｐ＜０．０５）;ＩＬ－２和ＩＬ－８则低于ＣＲＳ组（Ｐ＜０．０５;Ｐ＜０．０１）。结论ＭＴＤ血清和ＭＯＦ中ＩＬ－２、ＩＬ－６、ＩＬ－８和ＩＦＮγ活性反映了ＭＴＤ抗肿瘤免疫的功能状态。ＩＬ－６和ＩＬ－８活性对于ＭＴＤ预后的估计具有重要的意义。     

肝癌导向治疗的临床研究(1980～1999年临床研究总结)

目的　探讨核素 (或药物 ) 抗AFP抗体、1 31 I或 (1 2 5I) 抗AFP(AFP .McAb或AFPAb) MMC“双弹头”、1 2 5I LUF标记物治疗原发性肝癌病人的治疗效果及毒副反应。方法　 1 用改良氯胺T法将纯化AFP抗体标记核素1 31 I或1 2 5I获得标记物1 31 I(或1 2 5) 抗AFP抗体 ;用改良氨胺T法和过碘酸钠氧化法标记核素1 31 I或1 2 5I与MMC制备“双弹头” :1 31 I 抗AFP单抗 (AFP .McAb) MMC(称双弹头I)和1 31 I(或1 2 5I) 抗AFP多抗 (AFPAb) MMC(称双弹头Ⅱ ) ;催化置换反应制备1 2 5I 超液化碘油 (1 2 5I LUF) ;2 治疗后行肿瘤放射免疫定位显像 ;3 治疗 :1 94例进入临床试验 :1 31 I 抗AFP(n =72 ) ,1 2 5I 抗AFP(n =2 2 ) ,抗癌药 抗AFP(n =2 1 ) ,1 31 I或1 2 5I 抗AFP MMC(n =41 ) ,1 2 5I LUF(n =38)。结果　 1 治疗后病人瘤 /肝 (T/L)比值 ,以1 2 5I LUF(3 46) >双弹头 (2 2 6) >单一弹头 (1 5～ 2 5) ,T/L以ia途径 >iv ;2 早期研究的病例晚期者居多 ,1 31 I 抗AFP、1 2 5I 抗AFP和双弹头Ⅰ、Ⅱ治后 1年存率分别为 33 3 % (2 2 / 66)、47 1 % (8/ 1 7)和 58 5 % (2 4 / 4 1 ) ,以抗癌药 抗AFP最低 (1 9 0 % ) ,而1 2 5I LUF则高达 81 6 % (31 / 38) ,其中 1 8例加外照射者为 1 0 0 % (1 8/ 1 8)     

THE ROLE OF TARGETING THERAPY IN CYTOREDUCTION AND SEQUENTIAL RESECTION OF UNRESECTABLE HEPATOCELLULAR CARCINOMA

ＴＨＥＲＯＬＥＯＦＴＡＲＧＥＴＩＮＧＴＨＥＲＡＰＹＩＮＣＹＴＯＲＥＤＵＣＴＩＯＮＡＮＤＳＥＱＵＥＮＴＩＡＬＲＥＳＥＣＴＩＯＮＯＦＵＮＲＥＳＥＣＴＡＢＬＥＨＥＰＡＴＯＣＥＬＬＵＬＡＲＣＡＲＣＩＮＯＭＡＴａｎｇＺｈａｏｙｏｕ汤钊猷ＹｕＹｅｑｉｎ余业勤Ｚｈ...     

~（131）I美妥昔单抗治疗79例原发性肝癌的近期疗效及毒副作用观察

目的：总结131I美妥昔单抗（商品名：利卡汀）治疗中晚期原发性肝癌（HCC）的近期疗效及毒副作用。方法：已确诊的HCC患者79例,采用经肝动脉途径灌注利卡汀治疗。治疗后每月随访患者一般情况、影像学改变、甲胎蛋白（AFP）、肝功能、外周血白细胞、血小板变化等。对治疗前不同肝功能分级患者复发情况进行比较,评价近期疗效及毒副作用。结果：利卡汀治疗后71例随访的患者中1个月无复发率为100%,3个月无复发率为76.1%,6个月无复发率为28.2%。所有患者中死亡14例,占19.2%,中位生存时间8个月。均未发生与治疗药物相关的严重并发症。结论：131I美妥昔单抗用于不可手术切除肝癌患者,尤其是肝功能情况较好患者的疗效明显;是原发性肝癌治疗中的一种新型、有效的治疗方法。     

FACTORS INFLUENCING THE EFFECT OF RADIOIMMUNOTHERAPY ON LIVER CANCER

Factors influencing the therapeutic effect of radiolmmunotherapy with 131I labeled anti- human hepa-tocellular carcinoma (HCC) ferritin antibody (131I -FtAb) on thirty three patients with surgically proven unresectable HCC were studied. Multi- variable analysis with Cox' s regression model revealed that the statistically sig-nifieant factors include tumor size, activity of 131I administered each time and the second-look resection. Survival of patients with tumor diameter less than 10 cm was higher than that of patients with tumor diameter more than 10 cm (1-year survival; 84% versus 50%) 3-year survival; 63% versus 9% ). Patients administered with 5. 55×108 Bq to 9. 25× 10(?) of 131I-FtAb each time yielded better effect than those administered with more than 9. 25×108 Bq of 131I -FtAb (1-year, survival: 86% ver- sus 55%; 3-year survival: 50% versus 18%). When tumor shrank, patients underwent second-look resection had a higher survival than those without receiving second- look resection (1- year survi     

Radioimmunotherapy in the multimodality treatment of hepatocellular carcinoma with reference to second-look resection.

Experimental study using nude mice human hepatocellular carcinoma (HCC) xenograft indicated that the combination treatment with iodine 131 (131I)-anti-human HCC isoferritin (131I-isoFtAb), cisplatin, and mixed bacterial vaccine (MBV) yielded better inhibition rate as compared with double combination or 131I-isoFtAb alone. Based on these findings, 25 patients with surgically proven nonresectable and pathologically proven HCC have been treated by radioimmunotherapy using 131I-isoFtAb intrahepatic arterial infusion as a part of multimodality treatment. Of the 25 patients, seven (28.0%) received second-look resection after marked shrinkage of tumor. The 1-year survival was 52.5% (12/23) and 2-year survival 27.7% (five of 18) in the entire series. Of the five patients with 2-year survival, four were in the second-look resection group. Patients with tumor less than or equal to 8 cm showed higher second-look resection rate (62.5% versus 11.8%) and 1-year survival (85.7% versus 37.5%) as compared with tumor greater than 8 cm. Mixed bacterial vaccine as adjuvant immunotherapy seemed effective to prolong survival. The 2-year survival was higher in patients with second-look resection as compared with those without (75.0% versus 14.3%). Thus, radioimmunotherapy using 131I-isoFtAb might be one of the modalities of choice, particularly in the conversion of nonresectable to resectable HCC in a well-designed multimodality treatment regimen.     

Biodistribution and localization of iodine-131-labeled metuximab in patients with hepatocellular carcinoma

PURPOSE: Radioimmunotherapy may improve the outcome of hepatocellular carcinoma (HCC) patients by delivering targeted radiation to liver lesion tissue while relatively sparing nontarget tissues. This study was designed to observe the biodistribution, localization and imaging characteristics of 131I -labeled Metuximab in 24 patients with HCC to determine the diagnostic and therapeutic potential of this antibody. METHODS: Twenty-four HCC patients were randomly divided into three groups to receive 18.5, 27.75 and 37 MBq/kg of 131I-labeled Metuximab per kilogram of body weight, respectively. 99mTc-sodium phytate was administered intravenously and the single photon emission computed tomography (SPECT) scanning was performed. After 48 h, 131I -labeled Metuximab was injected by hepatic artery intubation, and SPECT scan performed at 7 d. The percentage of absorbed 131I (%ID) and the time-dependent 131I tumor:nontumor tissue (T/NT) ratios were calculated at 12, 48, 96 and 192 h after injection. RESULTS: The positive Imaging result of MAb scanning in 24 patients showed that the iodine 131 conjugated to Metuximab was apparently accumulated more in hepatoma. Biodistribution studies of 131I-Metuximab in trial I demonstrated that the comparable % ID uptake in tumor (with a T/NT ratio at 12, 48, 96 and 192 h) to that in such normal organs, as thyroid, heart, lung, spleen and intestines were all more than one. The optimal imaging time for the highest T/NT ratio in liver was at 192 h. CONCLUSION: 131I-labeled Metuximab could deliver relatively selective radiation to tumor tissues and may have potential efficacy in relieving hepatocellular carcinoma.     

Comparison between 131I and 111In as radiolabels for monoclonal antibodies in immunoscintigraphy of tumor bearing nude mice

F(ab')2 fragments of monoclonal antibody (MoAb) 19-9 with specificity for human colorectal adenocarcinomas were labeled with 111In or 131I and infused into nude mice bearing the human adenocarcinoma HT 29 in order to compare their preferential biodistribution according to the radiolabel used. Animal tissue distribution measured one day and five days after infusion showed that tumor accumulation was greater for 111In than for 131I. However, non specific binding of 111In labeled MoAb 19-9 was also greater in normal tissue than 131I labeled antibody, except in blood. Therefore, the tumor/normal tissue ratios were to the advantage of 131I MoAb 19-9 and a better contrast was obtained on imaging with 131I as compared to 111In labeled MoAb 19-9. Based on this experimental model 111In does not seem to be the optimal candidate for tumor imaging using radiolabeled MoAb.     

Internal radiation therapy for hepatocellular carcinoma. Results of a French multicenter phase II trial of transarterial injection of iodine 131-labeled Lipiodol.

Preliminary Phase I trials have shown iodine 131 (131I)-Lipiodol (ethiodized oil; Laboratoires Guerbet, Aulnaysous-Bois, France) to be well tolerated and most likely effective in the treatment of hepatocellular carcinoma (HCC). In this multicenter Phase II trial, the authors tested the feasibility and reproducibility of this treatment in other medical institutions and evaluated its efficacy in 50 patients with unresectable Stage I or II HCC, by the classification of Okuda et al. The authors studied 47 men and 3 women (63.9 +/- 7.1 years old) with Stage I (n = 18) or II (n = 32) HCC, by the classification of Okuda et al., which was verified by histologic findings (n = 25), cytologic findings (n = 11), or association of a tumor with alpha-fetoprotein serum values greater than 500 micrograms/l (n = 14). This multicenter trial (1) confirmed that the 131I-Lipiodol treatment is well tolerated; (2) showed that there is a high reproducibility of results with respect to other institutions and an objective tumor response in 40% of the cases; and (3) indicated the necessity of performing a randomized controlled study.     

Polyclonal and monoclonal anti-CEA antibodies in immunolocalization of colorectal cancer

Antibodies to carcinoembryonic antigen (CEA) from sheep and monkey were immunoadsorbent purified. Mouse monoclonal antibody (MAb) anti-CEA I-38S1 and Fab fragments of this antibody were prepared from mouse ascitic fluid. The IgG preparations were labelled with 123I or 131I, the Fab fragments with 131I. The antibody reactivity was unchanged after labelling. Patients with advanced colorectal carcinomas received an intravenous injection of 50-200 MBq 123I or 30-160 MBq 131I coupled to 250-500 micrograms antibody or antibody fragment. Patient examinations were performed using emission tomography (SPECT) and/or conventional gamma camera scintigraphy. The specific localization of labelled anti-CEA to tumor was compared to known tumor localized by CAT-scan, other x-ray methods or laparotomy, 50% of known tumors were accurately localized with sheep anti-CEA. In contrast, 70-80% of known tumor sites were correctly localized with polyclonal monkey anti-CEA antibodies, with monoclonal anti-CEA antibodies or with Fab fragments of the latter. A few previously unknown tumors were detected.     

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials

PURPOSE: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine (131I) metuximab injection (Licartin), a novel 131I-labeled HAb18G/CD147-specific monoclonal antibody Fab'2 fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. METHODS AND MATERIALS: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. RESULTS: No life-threatening toxic effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p = 0.0019). CONCLUSION: Iodine (131I) metuximab injection is safe and active for HCC patients.