生长抑素SMS201—995对小鼠结肠癌肝转移瘤的实验研究

本研究观察生长抑素衍生素ＳＭＳ２０１－９９５对ＢＡＬＢ／ｃ小鼠结肠腺癌肝转移瘤细胞周期的影响，检测血清ＣＥＡ水平的变化，并观察小鼠生存期的改变。采用流式细胞术。与对照组相比，ＳＭＳ２０１－９９５治疗组的瘤细胞增殖指数和Ｓ期细胞百分比明显降低（Ｐ〈０．０１）而Ｇ０／Ｇ１期细胞百分比则明显增加（Ｐ〈０．０１）。治疗组血清ＣＥＡ水平较对照组显著降低（Ｐ〈０．０５），生存期明显延长。治疗组细胞增殖指数，Ｓ     

骨髓增生异常综合征患者血清铜、锌水平及其与骨髓细胞增殖动力学关系的探讨

应用ＧＧＸ－Ⅱ型火焰原子吸收分光光度计测定５０例原发性骨髓增生异常综合征（ＭＤＳ）患者的血清铜（ＳＣｕ）和血清锌（ＳＺｎ）水平，其中２９例同时应用流式细胞仪测定了骨髓细胞增殖动力学，５０例年龄相似的健康人作为对照。结果显示；ＳＣｕ和Ｃｕ／Ｚｎ在ＭＤＳ明显高于正常对照，而ＳＺｎ则明显低于正常对照（Ｐ值均＜０．００１）。在ＭＤＳ各亚型间，ＳＣｕ和Ｃｕ／Ｚｎ在ＲＡＥＢ和ＲＡＥＢＴ组明显高于ＲＡ＋ＲＡＳ组（Ｐ值分别＜０．０１和０．０５）；ＳＣｕ水平与骨髓Ｓ＋Ｇ２Ｍ期细胞比例呈负相关（ｒ＝０．３８，Ｐ值＜０．０５），还讨论了血清铜增高的可能机制。     

TSP、VEGF与大肠癌血管生成、转移关系的研究

目的 分析小板反应素（ｔｈｒｏｍｂｏｓｐｏｎｄｉｎ,ＴＳＰ）、血管内皮生长因子（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｇｒｏｗｔｈ ｆａｃｔｏｒ,ＶＥＧＦ）表达和大肠癌血管生成、远处转移之间的关系。方法 对４７例大肠癌手术标本采用逆转录多聚酶链反应（ＲＴ－ＰＣＲ）检测ＴＳＰ１和ＴＳＰ２ｍＲＮＡ表达,并采用免疫组化法检测微血管计数（ｍｉｃｒｏｖｅｓｓｅｌ ｃｏｕｎｔ,ＭＶＣ）和ＶＥＧＦ蛋白表达。结果 大肠癌ＭＶＣ和ＶＥＧＦ表达的程度呈正相关（ｒ＝０．４３８,Ｐ＝０．００２）,在淋巴结转移和远处转移者高于无转移者（Ｐ〈０．０５）。ＴＳＰ２ｍＲＮＡ表害和ＭＶＣ（ｒ＝－０．３６２,Ｐ＝０．０１）、ＶＥＧＦ表达（ｒ＝－０．３２２,Ｐ〈０．０５）有明显的负相关。ＴＳＰ２ｍＲＮＡ表达率在远处转移病人中低于没有远处转移者（     

大肠癌患者血清中TGF-β1表达的意义

 目的研究大肠癌患者血清中转化生长因子β１（ＴＧＦ β１）表达意义及其与癌胚抗原（ＣＥＡ）、肿瘤分期的关系。方法以酶联免疫法检测血清中ＴＧＦ β１的含量。结果患者组血清ＴＧＦ β１（４０．３６±１７．６０ｎｇ／ｍｌ）高于对照组（１９．２±７．９８ｎｇ／ｍｌ）（Ｐ＜０．０１），ＴＧＦ β１的含量随着肿瘤分期增加而升高（Ｐ＜０．０５）且与血清中ＣＥＡ含量有关（ｒ＝０．３９２，Ｐ＜０．０１）。结论大肠癌患者血清ＴＧＦ β１含量与肿瘤的发生、发展有关。     

温热低渗液联合洗必泰卡铂对胃癌腹膜移植瘤增殖活性的影响

目的探讨温热低渗液、洗必泰、卡铂或联合应用,对Ｓｙ８６Ｂ人胃癌小鼠腹膜移植瘤增殖活性抑制作用及其与直接杀伤效应的相关性。方法采用Ｂｒｄｕ体外标记、ＦＣＭ及ＲＩＡ技术检测,经４３℃双蒸馏水（ＤＤＷ）、ＤＤＷ加微量洗必泰（０．０５％）、卡铂（１０ｍｇ／ｋｇ）和４３℃ＤＤＷ加卡铂（１０ｍｇ／ｋｇ）处理后的腹水瘤细胞增殖指标。结果与对照组比较,各实验组瘤细胞的Ｂｒｄｕ标记指数（ＢｒｄｕＬＩ）减少２１．８％～７５．０％（Ｐ＜０．０５～０．０１）;Ｓ和Ｇ２／Ｍ期增殖细胞比率、增殖指数（ＰＩ）和ＤＮＡ指数（ＤＩ）显著下降（Ｐ＜０．０１）。瘤细胞的异倍体与二倍体ＤＮＡ核型比例分别为６４,７３,４６和１９;腹水上清中ＣＥＡ和ｈＥＧＦ含量消减（Ｐ＜０．０１）。ＢｒｄｕＬＩ、ＰＩ、ＤＩ、ＣＥＡ和ｈＥＧＦ５种指标与小鼠生存时间或瘤细胞数量之间相关性有显著意义（ｒ＝０．４９～０．８２,Ｐ＜０．０５～０．０１）。结论４种处理因素均有抑制瘤细胞增殖活性作用,以４３℃ＤＤＷ协同卡铂效果最佳。     

微血管定量和血管内皮生长因子表达在肠型胃癌中的意义

为研究血管形成和血管形成因子表达在肠型胃癌和弥漫型胃癌中的作用，应用抗因子Ⅷ相关抗原抗体、抗ＶＥＧＦ抗体及抗ｂＦＧＦ抗体的免疫组化ＬＳＡＢ法，分别对６３例肠型胃癌和４５例弥漫型胃癌中的微血管数量（ＭＶＣ）、ＶＥＧＦ和ｂＦＧＦ表达进行研究。ＭＶＣ和ＶＥＧＦ及ｂＦＧＦ表达在肠型胃癌明显高于弥漫型胃癌（Ｐ分别＜０．０５，０．００１和０．０１），同样，ＭＶＣ和ＶＥＧＦ表达在肝转移患者明显高于腹膜转移者（Ｐ分别＝０．００１和＜０．０１）；在肠型胃癌中，ＭＶＣ与ＶＥＧＦ表达明显相关（Ｐ＝０．０２），ＭＶＣ和ＶＥＧＦ表达随ＴＮＭ分期增加而增加，而与弥漫型胃癌无关。两型胃癌中的ｂＦＧＦ表达均与ＭＶＣ无关。本研究结果表明肠型胃癌的转移形式为血管依赖性，ＶＥＧＦ可能是诱导肠型胃癌血管形成的一个重要因子。     

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。     

血清唾液酸检测对癌症诊断的临床价值

作者测定了５７７例正常人和２４１例恶性肿瘤患者血清总唾液酸（ＴＳＡ）和血清脂质结合唾液酸（ＬＳＡ）的含量。结果表明：ＴＳＡ和ＬＳＡ的含量变化与疗效一致，治疗有效者ＴＳＡ和ＬＳＡ与正常人相比，均无显著性差异（Ｐ＞０．０５）；治疗无效（包括未经治疗）者与正常人相比除原发性肝癌、乳腺癌外均有显著性差异（Ｐ＜０．０１）。血清ＴＳＡ和ＬＳＡ测定对肺癌、胃癌、大肠癌等有临床诊断价值（Ｐ＜０．０１），对鼻咽癌诊断效果更好（Ｐ＜０．００１）。对肝癌、乳腺癌的诊断价值有限（Ｐ＞０．０５）。恶性肿瘤患者ＴＳＡ与ＬＳＡ含量间无相关关系（ｒ＝０．０９；Ｐ＞０．０５；ｎ＝１１７）。ＬＳＡ检测不能代替ＴＳＡ检测，两者应该联合检测以提高其阳性率。     

表皮生长因子及其受体在胃癌患者中的表达

采用放射免疫法测定２６例胃癌病人血清、尿液ＥＧＦ水平，同时采用免疫组化ＳＡＢＣ法检测胃粘膜组织切片中ＥＧＦＲ染色的阳性率，并与正常对照进行比较分析。结果表明：胃癌患者血清和尿ＥＧＦ水平均显著高于正常对照（３．７２±１．８３μｇ／Ｌ与１．７７±０．６０μｇ／Ｌ，Ｐ＜０．０１；１８．４４±１７．８８ｎｇ／ｍｇ与５．１９±６．３７ｎｇ／ｍｇ，Ｐ＜０．０１），胃粘膜组织切片ＥＧＦＲ染色阳性率也明显高于正常对照（７３％与１１％，Ｐ＜０．０１）。胃癌病人中，ＥＧＦＲ染色阳性者血清ＥＧＦ水平显著高于ＥＧＦＲ阴性者（Ｐ＜０．０５），但两者尿ＥＧＦ水平无显著性差异。胃癌患者血清、尿ＥＧＦ水平与胃癌大小、分化程度及淋巴结转移无显著性相关。     

SF、β_2－MG、CEA对女性生殖器恶性肿瘤的临床意义

应用放射免疫法对６７例女性生殖器恶性肿瘤患者及３０例非恶性疾病患者进行ＳＦ、β２－ＭＧ、ＣＥＡ测定。结果表明：恶性肿瘤组ＳＦ、β２－ＭＧ、ＣＥＡ的阳性率分别为２５．８１％，１３．１％，１５％。其联合测定的综合阳性率为４３．３％，其中ＳＦ阳性率显著高于非恶性疾病患者（Ｐ＜０．０１）。恶性肿瘤患者治疗前后ＳＦ值比较差异有显著性意义（Ｐ＜０．００１）。而β２－ＭＧ、ＣＥＡ测定值无意义（Ｐ＞０．０５）。作者认为，ＳＦ测定对女性生殖器恶性肿瘤的诊断及疗效估价有一定的临床意义。     

Effect of a long-acting analogue of somatostatin, SMS 201-995, on the development of intestinal tumours in azoxymethane-treated rats

The effect of daily parenteral administration of a long-actinganalogue of somatostatin (SMS 201-995) on the development ofintestinal tumours and the rate of crypt cell proliferationin azoxymethane-treated rats has been studied. SMS 201-995 hadno significant effect on the number of colonic tumours induced.In the duodenum, SMS 201-995 administration was associated witha change in the number of tumours from 1.4/rat in saline-treatedanimals to 2.4/rat in animals treated for the last third ofthe study and 2.8/rat in animals treated with SMS for the entireduration of the study (P < 0.02). SMS had no significanteffect on the rate of cell proliferation in the duodenum, ileumor colon. The inhibition of release of gastrointestinal trophichormones by this analogue of somatostatin thus does not appearto reduce the number of tumours in the intestine of azoxymethane-treatedrats.     

The effect of the somatostatin analogue SMS 201-995 on experimental pancreatic carcinogenesis in the Syrian golden hamster

Somatostatin analogues have been suggested as possible therapy for human pancreatic cancer. This paper investigates the effect of the somatostatin analogue SMS 201-995 (Sandoz) in the Syrian golden hamster model of nitrosamine-induced pancreatic carcinogenesis. Step-wise increasing doses of i.v. SMS 201-995 suppressed pancreatic juice output from a median basal value of 212 mg/kg body wt/h (Q1:Q3 = 121:334) to a median basal value of 70 mg/kg body wt/h during infusion of 5 micrograms/kg body wt/h of SMS 201-995 (Q1:Q3 = 64:102, P less than 0.05). Chronic s.c. injection of 5 and 10 micrograms/kg body wt SMS 201-995 twice daily for 3 days each week, did not affect pancreatic wet wt or pancreatic total DNA content after 1 or 6 weeks of treatment when compared to controls. The most interesting and unexpected finding in our study was that SMS 201-995 seemed to promote pancreatic carcinogenesis when administered in low dosage. More SMS 201-995 treated animals receiving 5 micrograms/kg body wt developed invasive pancreatic adenocarcinoma than controls after 15 weeks of carcinogen (4/10 animals versus 0/10, P less than 0.05, Fisher's exact test) and pancreatic involvement by tumour was more extensive (17/75 pancreatic blocks affected versus 0/71, P less than 0.001). When carcinoma in situ and microcarcinomata were analysed with invasive lesions, animals injected with 5 micrograms/kg body wt SMS 201-995 were still significantly more affected than controls (33/75 blocks versus 9/71, P less than 0.001). Hamsters injected with the higher SMS 201-995 dose (10 micrograms/kg body wt) did not show any increase in malignancy over the controls. These results suggest that the effect of SMS 201-995 on pancreatic carcinogenesis in the Syrian hamster is complex and varies with dose administered. Further work is required before its use on man can be justified.     

Acromegaly from ectopic growth hormone-releasing hormone secretion by a malignant carcinoid tumor. Successful treatment with long-acting somatostatin analogue SMS 201-995

A 26-year-old man with acromegaly secondary to ectopic growth hormone-releasing hormone (GHRH) secretion by a metastatic carcinoid tumor is the subject of this study. He previously failed to respond to conventional therapeutic modalities (partial hypophysectomy, pituitary irradiation, high-dose bromocriptine and a combination of streptozotocin and 5-fluorouracil) and was treated with long-acting somatostatin analogue SMS 201-995 (Sandoz, East Hanover, NJ). Growth hormone and somatomedin C concentrations became normal, and GHRH-LI (GHRH-like immunoreactivity) was suppressed by more than 60%. The growth hormone response to exogenous GHRH 1-40 was stopped and growth hormone rise to thyrotropin-releasing hormone (TRH) was significantly attenuated. A significant shrinkage of the pituitary gland was observed. Similarly, the size of the metastatic carcinoid lesions decreased dramatically and was accompanied by a normalization of liver function. After almost 2 years of SMS 201-995 therapy, the patient was well and had no clinical signs of acromegaly. Thus, SMS 201-995 appears to be a remarkably effective agent for treatment of acromegaly secondary to ectopic GHRH secretion.     

The effects of sandostatin (Octreotide, SMS 201-995) infusion on splanchnic and hepatic blood flow in an experimental model of hepatic metastases.

Manipulation of hepatic blood flow may improve drug delivery to hepatic tumour. Somatostatin and its long acting analogues are known to elicit effects upon hepatic and splanchnic blood flow in experimental animals and patients with portal hypertension. This study investigates the effects of SMS 201-995 (sandostatin) infusion on hepatic, splanchnic and tumour blood flow in an experimental model of liver metastases. Hepatic tumour was induced by the intraportal inoculation of 10(6) HSN sarcoma cells and blood flow measured using the dual reference microsphere method before and after infusion of SMS 201-995. There was a significant decrease in hepatic arterial flow and a significant increase in the tumour:liver blood flow ratio associated with a marked reduction in blood flow to normal hepatic parenchyma. Portal venous inflow and tumour blood flow were not significantly affected. SMS 201-995 infusion may lead to preferential delivery of concomitantly injected cytotoxic drugs to hepatic tumour. In addition, the reduction in growth of hepatic tumour may be due to a reduction in nutritive, arterial blood flow to hepatic tumour.     

Effect of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) in advanced breast cancer

Sixteen post-menopausal patients with advanced breast cancer were treated with a long acting somatostatin analogue, SMS 201-995 (Sandostatin): 0.1 mg bid sub-cutaneously. The dose was chosen on the basis of efficiency in acromegaly treatment. SMS 201-995 activity was evaluated assaying Insulin Growth Factor 1 (IGF1) plasma concentration. A merely partial IGF1 decrease was noted. To be evaluable for response, patients had to be treated for at least 30 days. Among the 14 evaluable patients, we observed no response to SMS 201-995. However, we noted tumor stabilization in 3 patients after a 90 days treatment period. Side-effects were very mild. This first report on SMS 201-995 treatment of breast cancer suggests that further studies evaluating the effect of other modes of administration or drug association should be warranted.     

The effect of the E2 prostaglandin enprostil, and the somatostatin analogue SMS 201 995, on the growth of a human gastric cell line, MKN45G

The effect of enprostil and the somatostatin analogue SMS 201 995 on the growth of a clonal variant of the human gastric adenocarcinoma cell line, MKN45, was studied. The derived cell line grew twice as fast as MKN45 when grown as a xenograft line in nude mice. However, it did not respond trophically to gastrin either in vitro or in vivo (unlike MKN45) although it possessed the same number of gastrin receptors as the parental line. Gastrin production by the cell line during in vitro culture was twice that of MKN45; thus, the cell line was denoted MKN45G. When MKN45G was grown as xenografts in nude mice (n = 10/group), enprostil (20 micrograms/kg/day) significantly inhibited tumour growth when administered continuously by an osmotic mini-pump from day 1 to day 7 of a 20-day experiment, and induced tumour regression when administered from day 7 to day 14. Enprostil reduced postprandial serum gastrin levels when administered from day 7 to day 14 and prevented gastrin release by MKN45 in vitro. SMS 201 995 at doses of 25 and 240 micrograms/kg/day induced tumour regression when administered from day 1 to day 7 and the former dose reduced post-prandial serum gastrin levels at day 5. Gastrin release by MKN45G was not affected by SMS 201 995 in vitro, thus its effect may not be mediated directly via gastrin, requiring interaction between other hormones or growth factors in the in vivo situation.     

Desensitization and resensitization of rat pituitary tumor cells in long-term culture to the effects of the somatostatin analogue SMS 201-995 on cell growth and prolactin secretion

Cultured cells, prepared from the transplantable rat prolactin (rPRL)-secreting rat pituitary tumor 7315b were found to be inhibited in a dose-dependent way in their cell growth and hormone secretion by the somatostatin analogue SMS 201-995 (Sandostatin). In short-term (1 week) experiments these effects were not time dependent and of similar magnitude (an inhibition of approximately 50% at 100 nM SMA 201-995) both for the rate of rPRL secretion and for the rate of incorporation of tritiated thymidine into the tumor cells. When freshly isolated 7315b cells were used for long-term experiments (38 days), continuous exposure to SMS 201-995 at all concentrations tested (0.1 nM, 10 nM, and 1 microM) resulted in desensitization of the cells to the peptide with respect to rPRL secretion. Using a stable cell line derived from the long-term experiment and designated 7315c, we show that (a) long-term exposure of 7315c cells to SMS 201-995 leads to loss of sensitivity with respect to both rPRL secretion and cell growth, (b) this loss of sensitivity is accompanied by complete disappearance of the somatostatin receptors from the cells, (c) withdrawal of treatment from desensitized cells leads to reappearance of receptors and of sensitivity to SMS 201-995, showing that selection for a non-receptor-bearing population was not the cause of desensitization, and (d) since these experiments were carried out with a pure population of 7315c cells the effects of SMS 201-995 are direct effects on these cells and not effects mediated by other cell or organ systems.     

联合动态检测VEGF、CEA和CA199水平 及其与胃癌肝微转移的相关性

 目的 研究血清VEGF、CEA和CA199水平与胃癌肝微转移的相关性及其临床意义。方法 将168例胃癌患者分为未发生同时性肝转移组（未转移组）和发生同时性肝转移组（转移组）,分别在治疗前及治疗后第1、3、6、12、18、24月,采用ELISA法检测血清VEGF、CEA水平, 采用微粒子酶免分析法检测血清CA199水平。结果 治疗前血清VEGF、CEA、CA199阳性率未转移组和转移组分别为25.0%和87.5%、16.1%和51.8%、33.0%和50.0%,（P<0.01）。治疗后1、3、6、12、18、24月转移组VEGF、CEA、CA199的阳性率均明显高于未转移组。未转移组中无复发转移的患者43例、有微转移患者40例、有复发或肝外转移的患者29例,其CEA和CA199两者同时阳性率分别为30.2%、77.5%、75.9%, VEGF、CEA和CA199三者同时阳性率分别为34.8%、92.5%、86.2%。结论 联合动态检测胃癌患者的血清VEGF、CEA及CA199水平可以早期发现胃癌肝微转移。     

Combined treatment with TNP-470 and 5-fluorouracil effectively inhibits growth of murine colon cancer cells in vitro and liver metastasis in vivo

The combined effects of TNP-470 (TNP), a semisynthetic analogue of fumagillin, and 5-fluorouracil (5FU), a representative chemotherapeutic agent for colorectal cancer, were investigated using murine colon 26 adenocarcinoma (CT 26) cells. In a cell-proliferation study in vitro, 50% inhibitory concentrations (IC50) were determined to be 5.2 microg/ml and 240 ng/ml for TNP and 5FU, respectively. When CT 26 cells were treated with TNP and 5FU in combination, a remarkable cytotoxic effect was obtained. Isobologram analysis revealed synergism of these two agents in inhibition of the cell growth. In vivo, using a dorsal air sac assay, we found that TNP significantly inhibited the CT 26-induced angiogenesis. In addition, the combination of TNP and 5FU exerted a synergistic anti-tumor effect in a model of hepatic metastasis by portal injection of CT 26 cells. Since TNP is known to exert inhibitory effects on tumor cell growth through suppression of cell cycle progress from the G1 to S phases as well as neovascularization, it is speculated that the treatment with TNP enhanced the anti-tumor effect of 5FU through suppression of the cell cycle and tumor-derived angiogenesis. Taken together, these results suggest that combined treatment with TNP and 5FU is potentially useful for inhibition of tumor cell growth and liver metastasis of colorectal cancer.     

流式细胞术分析胃泌素对人结肠癌SW480裸鼠移植瘤的影响

目的：探讨胃泌素对人结肠癌裸鼠移植瘤的影响。方法：建立人结肠癌SW480裸鼠移植瘤模型,实验动物分为5肽胃泌素（PG）组及对照组,观察PG对移植瘤体积、重量的影响并进行流式细胞术分析。结果：移植瘤的体积重量、细胞内DNA、蛋白质含量、S期、G2M期细胞数、增殖指数PG组显著高于对照组,而G0／G1期细胞数则显著低于对照组。结论：胃泌素在体内具有促进人结肠癌SW480细胞分和增殖的作用,为结肠癌患者施行内分泌治疗提供了实验依据。