Stimulatory Effects of Retinoic Acid on Tumor Growth and Serum Insulin-like Growth Factor-1 in Rats Bearing Estrogen-responsive Pituitary Tumor MtT/Se

MtT/Se is one of 4 cell lines derived from an estrogen-dependent pituitary tumor, MtT/F84. The main difference between these tumor types is that MtT/F84 secretes both growth hormone (GH) and prolactin (PRL) whereas MtT/Se secretes only GH. MtT/Se grew slowly in ovariectomized (ovex) rats, but tumor growth was much faster in estrogen-treated ovex rats. Effects of dietary retinoic acid (RA) on tumor growth, serum GH and insulin-like growth factor-1 (IGF-1) levels were examined in ovex rats. Latency of tumor growth was shortened, and tumor take and weight were promoted by all- trans RA both in the presence and absence of exogenous estrogen. Serum GH and IGF-1 levels became increased in tumor-hearing rats whereas PRL levels remained unchanged. Serum IGF-1 levels exhibited a good correlation with tumor weights ( r =0.84). Our results suggest a close relationship between increase of tumor weight and stimulation of serum IGF-1 level by RA in tumor-bearing rats.     

Estrogen Receptor Levels and Tumor Growth in a Series of Pituitary Clonal Cell Lines in Rats

Four kinds of in vitro clonal pituitary tumor cell lines named MtT/Se, MtT/SM, MtT/S and MtT/ E, each of which shows different sensitivity to estrogen on proliferation, were inoculated into fat pad of ovariectomized rats and estrogen-loaded ovariectomized rats at 10⁵ and 10⁶ cells/site. They formed tumor with average latency ranging from 30 to 71 in ovariectomized rats and 13 to 63 days in estrogenized rats inoculated with 106 cells. MtT/Se was highly sensitive to estrogen for growth, and MtT/SM also grew well in estrogenized rats. With MtT/S and MtT/E, there was no significant shortening of average tumor latency in estrogenized rats. In vivo , the cytosolic estrogen receptor (ER) levels of MtT/Se, SM, S and E were measured to be 452 ±66, 370 ±115, 260 ±16 and 83 ±8 fmol/ mg protein, respectively. In vitro , however, the lowest ER level was noted in MtT/Se. Histologically, all four tumors grown in rats were composed of homogeneous round cells, and MtT/Se contained particularly large nucleated cells. In MtT/E, the cells appeared to be changing into ftbromatous cells. Three cell lines except MtT/E maintained the function of hormonal secretion in vivo as well as in vitro . Serum GH level was increased in rats with MtT/Se and MtT/S. Increased levels of both prolactin and growth hormone were measured in sera of rats with MtT/SM. Increases of hormones as well as tumor sizes were promoted by the estrogen.     

表皮生长因子对胶质瘤C6细胞垂体瘤转化基因影响的实验研究

目的探讨表皮生长因子（EGF）在体外对胶质瘤C6细胞垂体瘤转化基因（PTTG）表达的影响。方法不同浓度的EGF（10ng／mL、20ng／mL和30ng／mL）在体外作用于胶质瘤C6细胞,半定量逆转录聚合酶链式反应（RT—PCR）检测PTTG mRNA表达,Western检测其PTTG蛋白表达。结果与空白对照组比较,RT—PCR和Western检测结果显示PTTG mRNA及其蛋白的表达在各EGF作用组均显著增高,各组间比较差异有统计学意义（P〈0.01）。结论EGF可以量效的方式上调PTTG的表达。     

Modulation of Growth Factor Receptors on Acute Myeloblastic Leukemia Cells by Retinoic Acid

The effects of retinoic acid (RA) on the proliferation of acute myeloblastic leukemia (AML) cells were studied. AML samples were divided into three groups. Namely, RA stimulated blast colony formation by AML samples in group A and inhibited that by the samples in group B, regardless of added growth factors. For the samples in group C, RA inhibited the colonies formed by granulocyte colony-stimulating factor (G-CSF) but stimulated those by granulocyte macrophage CSF (GM-CSF). To investigate the mechanism involved, the effects of RA on growth factor receptors on AML cells were examined by flow cytometry using fluorolabeled ligands. For the samples in groups A and B, RA affected neither G-CSF receptor (GR) nor GM-CSF receptor (GMR). For the samples in group C, exposure to 10⁻⁷ MRA for 1 day clearly increased GMR, but did not affect GR. This finding supports the hypothesis that the increase of GMR is one of the causes of the stimulative effects of RA on cells cultured with GM-CSF in group C.     

维甲酸治疗胃粘膜癌前病变的实验研究

应用含０．０３％雷尼替丁的标准粉末状饲料和５０μｇ／ｍｌＭＮＮＧ联合喂饲大鼠共２０周，诱发胃粘膜病变。实验从第３６周起，按４０ｍｇ／ｋｇ体重，每日１次给大鼠喂服维甲酸共８周，之后处死动物进行观察。维甲酸治疗组大鼠胃粘膜肠化生、中重度异型增生及胃癌的发生率（各为７２．０％、２４．０％、０％）显著地低于未加治疗的对照组（各为１００．０％、５２．０％、１６．０％）（Ｐ＜０．０１、Ｐ＜０．０５）；维甲酸治疗组大鼠，病变胃粘膜血流量改善，泌酸功能显著好转，血和组织中ＬＰＯ含量明显下降，跨膜电位差恢复接近正常水平；维甲酸服用组大鼠未见明显毒副反应。表明维甲醇对大鼠实验性胃粘膜癌前病变有一定的治疗作用，清除自由基可能为其作用机理之一。     

Pharmacokinetics of All-trans Retinoic Acid in Pediatric Patients with Leukemia

Since all- trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), and its effectiveness appears to be related to the plasma or serum level, a pharmacokinetic study of ATRA was undertaken in nine patients with various leukemias. After oral administration at a dose of 30 mg/m², the time required to reach the peak plasma level of ATRA (20–1198 ng/ml) was between 120 and 240 min and the apparent plasma elimination half life was 21–51 min. In addition, 13-cis retinoic acid was detected in the plasma of seven patients, indicating the occurrence of ATRA isomerization in vivo. ATRA therapy did not induce complete remission in all patients, even when high plasma levels were achieved. Among the six APL patients given ATRA therapy, one who failed to respond had a very low plasma ATRA level. These findings suggest that it may be useful to monitor plasma levels during oral ATRA therapy in order to achieve an appropriate treatment regimen.     

维甲酸对小鼠前胃癌细胞恶性表型及抑癌基因表达的调控作用

采用全反式维甲酸（ＲＡ）对小鼠前胃癌细胞系进行了体外加药处理及将处理的细胞接种于近交系６１５小鼠皮下的实验观察。结果表明：经维甲酸处理的瘤细胞基本丧失在软琼脂中生长形成集落的能力，将该处理细胞接种于小鼠皮下，可见其自发性转移能力明显降低。ＲＮＡ狭线杂交显示经ＲＡ处理的瘤细胞其抑癌基因ｐ５３和转移抑制基因ｎｍ２３的表达明显增强，提示ＲＡ可能通过调控抑癌基因的表达，降低肿瘤细胞的转移能力。     

Experience with 9-Cis Retinoic Acid in Patients with Relapsed and Refractory Non-Hodgkin's Lymphoma

We conducted a phase II study to determine the efficacy and toxicity of 9-cis-retinoic acid (9-cis RA), a pan-retinoid receptor agonist, in the treatment of patients with relapsed and refractory NHL. Patients were eligible if they had histologically documented relapsed or refractory T cell or indolent B cell NHL. The first three patients enrolled received 70 mg/m² of 9-cis RA orally twice a day, but the remaining patients received a single oral daily dose of 100 mg/m². After 6 weeks of therapy, tumor response was assessed objectively. Response rate and toxicity were determined in all 29 eligible patients based on an intent-to-treat analysis. Four patients (14%) responded (3 PRs and 1 CR; 95% CI 4%- 33%). One patient had a minor response, and eight had stable disease. Responses were observed in two (11%) of 19 patients with B-cell lymphoma and in two (20%) of 10 patients with T-cell lymphoma. The median time-to-treatment failure for the 29 eligible patients was 8 weeks. The most frequent toxic effects were dry skin, headache, hypertriglyceridemia, and hypercalcemia. Five patients discontinued therapy due to toxic side effects, but no toxic deaths occurred during the study. We conclude that 9-cis RA has a modest activity in relapsed and refractory NHL. In this study, responses were observed in patients with B-cell lymphomas and those with T-cell lymphomas.     

肿瘤细胞染色质雌激素受体检测

采用E_2-HRP方法检测人肝细胞癌、胃癌、人胚肝、脑和脾组织的细胞染色质中雌激素受体(ER)并定位,发现这两种癌细胞染色质中都存在ER,但在上列入胚组织中均未测出。这一初步结果如能得到进一步阐明,将有助于了解ER在肿瘤发生与发展过程中作用的分子生物学机理。     

经单鼻蝶入路手术治疗垂体瘤的疗效观察

目的观察经单鼻蝶入路手术治疗垂体瘤的临床疗效。方法将40例垂体腺瘤患者随机分为观察组和对照组,每组20例。观察组采用显微镜下经单鼻蝶入路手术治疗,对照组采用经颅手术治疗,比较2组患者的临床疗效。结果观察组患者疗效明显优于对照组（P〈0．05）。结论经单鼻蝶入路手术治疗垂体瘤疗效较好,值得临床推广应用。     

侵袭性垂体腺瘤相关抑癌基因研究进展

侵袭性垂体腺瘤是一类特殊的垂体腺瘤,可向周围组织侵犯,危害性大,但发病机制未明。目前已证实垂体腺瘤是由单克隆发生的,可能由原始干细胞基因突变导致细胞增殖引起,即可能与抑癌基因的突变密切相关。因此,对侵袭性垂体腺瘤相关抑癌基因的研究至关重要。为在分子生物学层面研究垂体腺瘤侵袭性机制提供科学依据。     

姜黄素对马兜铃酸诱发的膀胱肿瘤的预防作用

 目的 以马兜铃酸诱发的膀胱癌为模型，观察姜黄素对膀胱组织的病理变化、Ras蛋白和p53蛋白及细胞角质蛋白20（CK20）的变化，评价姜黄素对马兜铃酸诱导膀胱癌的化学预防作用及发生机制。方法 50只大鼠随机分为对照组、诱癌组、预防组三组。诱癌组：给予10mg（kg·d）马兜铃酸给大鼠灌胃,连续诱癌3个月；预防组：在诱癌的同时给予含2%姜黄素粉的饲料进行化学防护；对照组：为正常饮食和饮水。3个月后宰杀全部大鼠，取膀胱组织进行HE染色显微镜下观察病理变化，用免疫组化染色技术检测膀胱组织内Ras、p53蛋白的变化，荧光定量PCR技术检測CK20 mRNA。结果 经3个月诱癌，膀胱癌的发生率在诱癌组为95% (19／20)，而姜黄素预防组，膀胱癌的发生率仅为10%（2/20），对照组膀胱黏膜组织Ras、p53蛋白及CK20 mRNA均呈阴性表达，预防组及诱癌组膀胱黏膜组织Ras、p53蛋白及CK20 mRNA均呈阳性，且以诱癌组更明显，差异具有统计学意义（P<0.001）。结论 姜黄素对马兜铃酸诱导的膀胱癌具有良好的化学预防作用，可能分子机制与抑制 Ras、p53蛋白的过度表达能力有关。姜黄素有望成为一种有应用前景的膀胱癌预防药物。     

维甲酸和甘草酸联合对人肺癌细胞增殖和侵袭抑制作用的研究

目的　探讨全反式维甲酸和甘草酸单独及联合作用对高转移人肺癌细胞 (PGCL3 )增殖和侵袭的抑制作用。方法　用维甲酸和甘草酸处理PGCL3细胞 ,通过细胞增殖抑制试验、软琼脂集落形成试验、侵袭、运动和黏附试验、以及组织蛋白酶B活性的测定 ,观察PGCL3细胞增殖和侵袭能力的变化。结果　维甲酸和甘草酸可减弱PGCL3细胞增殖能力 ,并呈剂量依赖性 ,半抑制浓度IC50 分别为 12 .6μmol/L和 1.8mmol/L。 2 .5 μmol/L和 5 .0 μmol/L维甲酸、0 .5mmol/L和 1.0mmol/L甘草酸能抑制PGCL3细胞的侵袭能力 (P <0 .0 5和P <0 .0 1) ,且有剂量依赖性。 5 .0 μmol/L维甲酸和 0 .5mmol/L甘草酸联合作用对PGCL3细胞的侵袭抑制率高于两药单独作用之和 ,呈协同作用。上述浓度甘草酸对细胞的运动、黏附、组织蛋白酶B分泌和软琼脂集落形成率均有显著抑制作用 (P <0 .0 1)。结论　维甲酸和甘草酸对PGCL3细胞的增殖和侵袭有抑制作用 ,两药有协同作用 ,甘草酸抗侵袭机理不是对侵袭的某一环节的阻断 ,而是对侵袭各个基本环节都有抑制作用     

维甲酸对大肠粘膜细胞增殖力学变化的影响

通过应用维甲酸对大鼠大肠癌的诱发过程进行干预治疗，旨在观察维甲酸对大肠粘膜细胞增殖力学变化的影响。结果显示，维甲酸治疗组（Ⅱ组）大肠癌的发生率显著低于未加维甲酸治疗的对照组（Ⅰ组）。在诱癌的中晚期ＰＣＮＡ指数及ＡｇＮＯＲ数亦显著低于Ⅰ组（Ｐ＜０．０１）。Ⅰ、Ⅱ组的ＰＣＮＡ指数和Ａｇ－ＮＯＲ数显著高于未用诱癌剂的Ⅲ、Ⅳ组（Ｐ＜０．０１）。组内对比结果显示，Ⅰ组ＰＣＮＡ指数和ＡｇＮＯＲ数有随着诱癌时间延长而增加的趋势，差异有显著性（Ｐ＜０．０５），而Ⅱ、Ⅲ、Ⅳ组内比较差异无显著性（Ｐ＞０．０５）。本组结果表明，维甲酸可完全或部分阻断实验性大肠癌的癌变过程，降低大肠癌的发生率。对临床应用维甲酸预防和治疗大肠癌提供了有意义的资料。     

Effect of Alcohol Ingestion on Carcinogenesis by Synthetic Estrogen and Progestin in the Rat Liver

We examined the effect of alcohol ingestion on hepatocarcinogenesis induced hy oral administration of synthetic female hormones, 0.075 mg of ethynylestradiol (EE) and 6.0 mg of norethindrone acetate (NA), every day for 12 months in female Wistar rats. Administration of 10% ethanol in drinking water for 5 days a week every week resulted in the development of hepatocellular carcinoma (HCC) in 38.4% of the hormone-treated rats at 12 months, which is approximately 5 times the incidence of HCC observed following EE and NA treatment alone. The number of hyperplastic nodules was significantly higher than the number observed in the case of EE and NA treatment alone after 4 months of the experimental period. The additional alcohol treatment also increased the value of unoccupied nuclear estrogen receptors (ERn) at months 6 and 8 of the experimental period, and increased the value of total ERn in the rat liver after 6 months of the experimental period. This indicates that additional alcohol treatment may increase occupied ERn (estrogen-ER complex) in the rat liver. A ³²P-postlabeling analysis of liver DNA revealed that the maximum number of extra spots consisting of modified nucleotides induced by EE and NA appeared earlier when the additional alcohol treatment was imposed. Consequently, alcohol affects the hepatocarcinogenesis by EE and NA, promoting not only the change in kinetics of ER, but also DNA adduct formation induced by EE and NA in the rat liver.     

藤黄酸对肿瘤细胞诱导分化作用的探讨

目的 观察藤黄酸对肿瘤细胞的诱导分化作用。方法 从增殖能力。细胞形态和功能变化3个方面评价藤黄酸对肿瘤细胞的诱导分化作用。结果 藤黄酸可提高K562细胞的Hb含量，降低B16细胞黑色素含量，抑制Bel7402细胞增殖并在形态上有趋向分化的改变。结论 实验显示藤黄酸有诱导肿瘤细胞分化的作用。     

维甲酸诱导分化在分化型甲状腺癌治疗中的初步应用

目的探讨分化型甲状腺癌（DTC）放射性碘治疗过程中应用维甲酸（RA）治疗的作用。方法20例患者在^131I治疗期间由于全身^131I扫描显示肺或骨转移灶不摄取碘或摄碘能力不够不足以达到治疗目的，在下一次治疗前1．5个月服用RA。将RA治疗后^131I摄取较前增加的病例归为治疗有效组，而RA治疗后无^131I摄取或同前相比^131I摄取无变化的病例归为治疗无效组。应用配对t检验来比较RA治疗前后血清甲状腺球蛋白（Tg）的变化。结果20例患者共计25例次在^131I治疗期间服用RA，其中11例次（44％）治疗有效。治疗有效组的中位Tg值（382-1000ng／ml）较治疗无效组（176．35～616．25ng／ml）增高明显，但治疗前后Tg值进行统计学比较没有显著性意义（P〉0．05）。结论RA治疗能恢复DTC细胞的摄碘功能。     

肿瘤细胞中HER2与脂肪酸合酶的关系

脂肪酸代谢和机体的能量平衡与肿瘤发生发展密切相关。脂肪酸合成酶（fatty acid synthase, FASN）作为一个代谢性癌基因,是能量链中的核心分子。近年来不少研究发现FASN和人表皮生长因子受体2（human epidermal growth factor receptor 2, HER2）之间存在双向分子联系,共同促进癌细胞转化、增殖、侵袭、转移、耐药等。本文对肿瘤细胞中二者相互作用作一综述。     

Granulocyte-colony Stimulating Factor and Retinoic Acid Cooperatively Induce Granulocytic Differentiation of Acute Promyelocytic Leukemia Cells in vitro

The interaction of granulocyte-colony stimulating factor (G-CSF) and retinoic acid (RA) in proliferation and differentiation of acute promyelocytic leukemia (APL) cells was examined. G-CSF stimulated proliferation of APL cells at concentrations of 0.1 to 50 ng/ml in a dose dependent manner. More than 10⁻⁸ M RA induced granulocytic differentiation of APL cells. Although G-CSF induced lysozyme activities in APL cells, it alone did not induce terminal differentiation of APL cells. G-CSF significantly enhanced the RA-induced granulocytic differentiation of APL cells in vitro. Enhancement by G-CSF was not due to the prolongation of survival of RA-induced differentiated cells, but the differentiation-inducing effects of G-CSF might be evident only in the presence of RA. Since G-CSF has a potential to induce the granulocytic differentiation of myeloid leukemia cells, G-CSF in combination with RA may be applicable in differentiation induction therapy for some types of myeloid leukemia.