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Studies on the disposition of 2,3-dihydro-1H-imidazo [1,2-b] pyrazole in rodents 2,3-二氢- 1h -咪唑[1,2-b]吡唑在啮齿动物体内的分布研究
Pub Date : 1981-04-01 DOI: 10.1016/0014-2964(81)90247-4
D.Dale Shoemaker, Ovella C. Ayers, Mary Ellen D'Anna, Richard L. Cysyk

2,3-Dihydro-1H-imidazo [1,2-b] pyrazole (IMPY, NSC-51143) is a new ribonucleotide reductase inhibitor, presently undergoing clinical evaluation, that exhibits prolonged in vivo antitumor activity in experimental animals. Disposition studies were initiated to determine if the prolonged in vivo antitumor activity of IMPY could be explained by its pharmacologic properties. Plasma disappearance curves of radioactivity were biphasic after the i.v. administration of 100, 250 or 500 mg/kg to rats and 250 mg/kg to mice. The distribution phase was rapid in each case (t12 of approximately 30 min or less), followed by a prolonged elimination phase. Radioactivity was distributed to all tissues of rats and mice including brain after an i.v. dose of 250 mg/kg. In rats, 67.8% of the administered radioactivity was excreted in the urine during the first 24 hr. By 120 hr 74.3% had been excreted via the urine compared with 11.1% in the fees, the latter by biliary excretion. The chromatographic profile of the urine collected from rats and mice 4 hr after drug administration indicated extensive metabolism. Thus, the prolonged plasma and tissue levels of parent IMPY and its metabolites can account for the prolonged duration of cytotoxic activity in vivo.

2,3-二氢- 1h -咪唑[1,2-b]吡唑(IMPY, NSC-51143)是一种新的核糖核苷酸还原酶抑制剂,目前正在进行临床评估,在实验动物中显示出持久的体内抗肿瘤活性。为了确定IMPY体内抗肿瘤活性的延长是否可以用它的药理学特性来解释,研究人员开始了处置研究。大鼠静脉给药100、250、500 mg/kg,小鼠静脉给药250 mg/kg,血浆放射性消失曲线呈双相变化。每个病例的分配阶段都很迅速(大约30分钟或更短),随后是一个延长的消除阶段。静脉注射剂量为250 mg/kg后,放射性分布到大鼠和小鼠的所有组织,包括脑。在大鼠中,67.8%的放射性物质在前24小时随尿液排出。到120小时时,74.3%通过尿液排泄,而费用为11.1%,后者通过胆道排泄。给药后4小时收集的大鼠和小鼠尿液的色谱图谱显示广泛的代谢。因此,母体IMPY及其代谢物的血浆和组织水平的延长可以解释体内细胞毒性活性持续时间的延长。
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引用次数: 3
Appearance of iron free hyperplastic hepatocytes following ferric nitrilotriacetate and 2-acetaminofluorene sequential administration 硝酸三乙酸铁和2-乙酰氨基芴序贯给药后无铁增生肝细胞的外观
Pub Date : 1981-04-01 DOI: 10.1016/0014-2964(81)90259-0
Gino Malvaldi
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引用次数: 6
Phase II evaluation of chlorozotocin (NSC-178248) in advanced human cancer 氯佐菌素(NSC-178248)治疗晚期人类癌症的II期评价
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90125-0
Robert W. Talley , Michael K. Samson , Robert W. Brownlee , Ahmad M. Samhouri , Roberto J. Fraile , Laurence H. Baker

A phase II evaluation of chlorozoticin (CZT), a water soluble nitrosourea, was undertaken to determine its effectiveness and toxicity in a variety of human metastatic neoplasms. The dosage regimen chosen was either 90 or 120 mg/m2 given by i.v. bolus every six weeks. Dosage escalation or de-escalation was dependent on toxicity. There have been 152 patients evaluable for response. The only significant response rates observed were in non-Hodgkin's lymphoma (5/11) and sarcoma (4/27). Single responses were observed in breast and oat cell carcinoma of lung. No responses were observed in melanoma, colorectal, kidney, non-oat cell lung, pancreas, stomach and other carcinomas. Hematological toxicity has been minimal as predicted, but does appear to be cumulative. The major G.I. toxicity has been nausea and vomiting—usually controllable. Occasional hepatic enzyme elevations were observed, and azotemia was observed in 6 patients. Both were reversible. Rare skin and occasional CNS reactions were also seen.

氯代虫胺(CZT)是一种水溶性亚硝基脲,进行了II期评估,以确定其对多种人类转移性肿瘤的有效性和毒性。给药方案为90或120 mg/m2,每6周静脉注射一次。剂量的增加或减少取决于毒性。有152例患者可评估反应。唯一观察到显著缓解率的是非霍奇金淋巴瘤(5/11)和肉瘤(4/27)。在乳腺癌和肺燕麦细胞癌中观察到单一反应。在黑色素瘤、结直肠癌、肾癌、非燕麦细胞肺癌、胰腺、胃等癌中均未见应答。血液学毒性如预测的那样很小,但似乎是累积的。G.I.的主要毒性是恶心和呕吐——通常是可控的。偶有肝酶升高,6例出现氮血症。两者都是可逆的。罕见的皮肤和偶尔的中枢神经系统反应也可见。
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引用次数: 10
The effect of liposome (phospholipid vesicle) entrapment of actinomycin D and methotrexate on the in vivo treatment of sensitive and resistant solid murine tumours 脂质体(磷脂囊)包裹放线菌素D和甲氨蝶呤在体内治疗敏感和耐药实体小鼠肿瘤中的作用
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90119-5
S.B. Kaye , Joan A. Boden , Brenda E. Ryman

When tested in mice bearing the Ridgway osteosarcoma (ROS) the activity of methotrexate entrapped in small cationic liposomes was increased, both in terms of tumour growth inhibition and toxicity for normal tissues. Conversely, actinomycin D entrapped in small cationic liposomes lost its cytotoxic activity, both against the tumor and normal tissues. In addition, liposome-entrapped actinomycin D proved ineffective therapeutically against a new ROS tumour subline in which resistance to free drug had been derived in vivo; moreover, this resistance appeared to have resulted from failure to retain drug rather than through impaired drug uptake. These results, and those obtained from tissue distribution studies using free and liposome-entrapped actinomycin D, suggested that (a) liposome entrapment modifies the pharmacokinetics and hence activity of these drugs by acting as a slow release system rather than by providing a means of selective delivery to tumours, and (b) the use of liposome-entrapped actinomycin D to overcome drug resistance acquired in vivo may be inappropriate.

当对患有里奇韦骨肉瘤(ROS)的小鼠进行测试时,捕获在小阳离子脂质体中的甲氨蝶呤的活性在抑制肿瘤生长和对正常组织的毒性方面都有所增加。相反,被包裹在小阳离子脂质体中的放线菌素D失去了对肿瘤和正常组织的细胞毒性活性。此外,脂质体包裹的放线菌素D被证明对一种新的ROS肿瘤亚群无效,该亚群在体内已经产生了对游离药物的耐药性;此外,这种耐药性似乎是由于未能保留药物而不是由于药物摄取受损。这些结果,以及使用游离和脂质体包裹的放线菌素D进行组织分布研究获得的结果表明:(a)脂质体包裹改变了这些药物的药代动力学,从而通过作为一个缓慢释放系统而不是通过提供一种选择性递送到肿瘤的手段来改变这些药物的活性;(b)使用脂质体包裹的放线菌素D来克服体内获得的耐药性可能是不合适的。
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引用次数: 28
Vincristine and bleomycin do not interfere with infusional plasma levels of methotrexate 长春新碱和博来霉素不干扰输注血浆甲氨蝶呤水平
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90129-8
L. Ottolenghi , E. Piazza , S. Marsoni , A. Trabattoni , N. Natale , M. Recchia , L. Morasca
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引用次数: 1
Histologic subtypes of small cell carcinoma of the lung: Response to therapy 肺小细胞癌的组织学亚型:对治疗的反应
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90127-4
Stephen Davis , Harold Sobel

Seventy-seven patients with extensive small cell carcinoma of the lung were initially treated with the same combination chemotherapy consisting of cyclophosphamide and doxorubicin. All cases were retrospectively subdivided according to their histological subtype as proposed by the World Health Organization Lung Cancer Classification (WHO): the classic lymphocyte-like (oat cell), type 21, and intermediate cell, type 22. Type 21 has an objective response rate of 43% and type 22 a response rate of 23%. Analysis of the data revealed that the median survival for WHO type 21 was 30.4 weeks; whereas median survival for type 22 was 17.2 weeks (P = 0.04). This difference in subtype response was also seen when response was corrected for Karnofsky initial performance status 40–70 but not for performance status 80–100. Type 21 small cell carcinoma appears to offer a higher response rate to chemotherapy and a longer survival than type 22.

77例肺广泛小细胞癌患者最初接受由环磷酰胺和阿霉素组成的相同联合化疗。根据世界卫生组织肺癌分类(WHO)提出的组织学亚型对所有病例进行回顾性细分:经典淋巴细胞样(燕麦细胞)21型和中间细胞22型。21型的客观反应率为43%,22型的反应率为23%。数据分析显示,WHO 21型的中位生存期为30.4周;而22型患者的中位生存期为17.2周(P = 0.04)。当Karnofsky初始成绩状态40-70而80-100的反应被纠正时,也可以看到这种亚型反应的差异。21型小细胞癌似乎比22型对化疗有更高的反应率和更长的生存期。
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引用次数: 4
Immunological characterization of cell lines established from malignant and normal human urothelium 恶性和正常人尿路上皮细胞系的免疫学特性
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90123-7
M. Vilien , H. Wolf , F. Rasmussen

Cell lines from normal or malignant human urothelium, described elsewhere by morphological, cell kinetic and genotypical criteria, have been characterized further by their response to antibody or lymphocyte mediated cytotoxicity in vitro. Four groups of cell lines were included: (1) two fast proliferating cell lines from normal urothelium, (2) three fast proliferating cell lines from transitional cell carcinoma (TCC) together with two transformed sublines of normal derived cell lines, (3) six slowly proliferating TCC lines, and (4) a line from squamous cell carcinoma. HLA antigen expression was demonstrated in the cell lines of groups 1 and 3, but not in lines from group 2 or 4. The sensitivity to spontaneous lymphocyte mediated cytotoxicity (SLMC) of cells in group 1 and 2 exceeded that of cells from group 3 by a factor of 8. The TCC line, HU 456, was more susceptible to SLMC than T 24. Specifically increased cytotoxicity of lymphocytes from patients suffering from interstitial cystitis (IC) against HU 609 from normal urothelium indicated that this line expresses tissue specific antigens, and at the same time that an immune reaction may be part of the pathogenesis of IC. By a sensitive test for antibody-dependent, cell-mediated cytotoxicity (ADCC) antibody activity against HU 456 was found in only one of nine TCC patients and none of five clinical controls. A pronounced non-disease-related blocking serum activity, frequently found, may account for some of the negative findings. The SLMC against HU 456 could be inhibited but not abolished by Fab fragments of rabbit anti-human immunoglobulin, indicating an ADCC mechanism as part of the SLMC.

来自正常或恶性人类尿路上皮的细胞系,在其他地方通过形态学、细胞动力学和基因型标准描述,已经通过其对抗体或淋巴细胞介导的体外细胞毒性的反应来进一步表征。包括四组细胞系:(1)两个来自正常尿路上皮的快速增殖细胞系,(2)三个来自移行细胞癌(TCC)的快速增殖的细胞系以及两个正常来源细胞系的转化亚系,(3)六个缓慢增殖的TCC系,和(4)一个来自鳞状细胞癌的细胞系。HLA抗原表达在第1组和第3组的细胞系中得到证实,但在第2组或第4组的细胞株中没有得到证实。第1组和第2组的细胞对自发淋巴细胞介导的细胞毒性(SLMC)的敏感性比第3组的细胞高出8倍。TCC系HU 456比T 24更易感染SLMC。来自间质性膀胱炎(IC)患者的淋巴细胞对来自正常尿路上皮的HU 609的特异性细胞毒性增加表明该系表达组织特异性抗原,同时免疫反应可能是IC发病机制的一部分。通过对抗体依赖性、细胞介导的针对HU 456的细胞毒性(ADCC)抗体活性的敏感测试,仅在9名TCC患者中的1名和5名临床对照中的1例中发现。经常发现的明显的非疾病相关的阻断血清活性可能是一些阴性结果的原因。兔抗人免疫球蛋白的Fab片段可以抑制但不能消除针对HU 456的SLMC,这表明ADCC机制是SLMC的一部分。
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引用次数: 10
Third European organization for research on treatment of cancer-national cancer institute symposium on new drugs in cancer therapy 第三届欧洲癌症治疗研究组织-癌症研究所癌症治疗新药研讨会
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90132-8
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引用次数: 0
Dr. Joseph P. Geraci's letter to the editor Joseph P.Geraci博士给编辑的信
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90131-6
K. Breur, G.W. Barendsen, J.J. Broerse
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引用次数: 0
Preoperative chemotherapy for operable solid tumours 可手术实体瘤的术前化疗
Pub Date : 1981-03-01 DOI: 10.1016/0014-2964(81)90117-1
Anaxagoras N. Papaioannou

Accumulating evidence suggests that most common solid tumours in man have latent metastases when clinically detected. Further evidence indicates that when the primary focus is resected, its micrometastases may become enhanced as a result of immunosuppression and other tumour-promoting factors at work in the perioperative period. In this favourable setting, the development of new metastases may also be facilitated from cells forced into the circulation during operative manipulations. It is suggested that the above events are important in the treatment outcome and that they may be prevented to some extent if treatment is first directed to the systemic component of these tumours; resections of the primary focus can be more advantageously done later. Results from experimental and clinical studies as well as many theoretical considerations support the potential value of this approach in the management of operable solid tumours.

越来越多的证据表明,大多数常见的人类实体瘤在临床检测时有潜在的转移。进一步的证据表明,当原发病灶被切除时,其微转移可能由于免疫抑制和其他促瘤因子在围手术期的作用而增强。在这种有利的环境下,在手术操作期间被迫进入循环的细胞也可能促进新转移的发展。建议上述事件在治疗结果中是重要的,并且如果治疗首先针对这些肿瘤的系统组成部分,它们可能在一定程度上得到预防;切除主要病灶可以在以后进行。实验和临床研究的结果以及许多理论考虑都支持这种方法在可手术实体肿瘤治疗中的潜在价值。
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引用次数: 21
期刊
European Journal of Cancer (1965)
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