Expression of c-raf-1 and A-raf-1 during regeneration of rat liver following surgical partial hepatectomy

The major objective of this study was to investigate the expression of members of the raf family of proto-oncogenes during rat liver regeneration. The steady-state level of expression of both c-raf-1 and A-raf-1 increased three- to fivefold 18-24 h following partial hepatectomy, and it returned to basal levels by 72 h. Expression of c-myc and Ha-ras mRNA was increased at 3 and 18-24 h, respectively, confirming previous reports. Increased steady-state levels of c-raf-1, A-raf-1, and Ha-ras mRNA were also detected in hepatocytes isolated from rat liver 24 h after partial hepatectomy. Thus, elevated expression of the raf genes closely correlated with that of Ha-ras, beginning at 12 h and reaching maximal levels during the first peak of DNA synthesis following partial hepatectomy.     

What's New in Proliferation and Differentiation in Malignant Tumours?

The volume of a tumour is the difference between the integrals of cell production and cell loss. Cell production depends on mitosis. Cells are lost by detachment from external surface, loss into blood vessels and lymphatics and into body cavities. Immunological lysis, macrophagia and apoptosis take place, and there is necrosis due to hypoxia. Cell birth can be measured, cell loss must be calculated. Tumour cells differentiate and mature to varying degrees. An inverse relationship between maturation and proliferation exists. DNA synthesis inhibitors often also induce differentiation. Retrodifferentiation does not take place. Immature tumours are undifferentiated because of a population change, not because of retrodifferentiation. The oncogene theory assumes that proto-oncogenes are part of the normal genome. They can be activated to oncogenes by mutation or by loss of regulatory factors. Oncogenes code for important membrane proteins: growth factors or receptors. It has been proposed that anti-oncogenes also exist, coding for inhibitory growth factors like chalones. Much attention has hitherto been directed to attempts at arresting the birth rate of cells by cytostatic drugs. There is a trend in modern research to find substances that can force the cells into maturation. Lithium, DMSO, vitamin-analogues, human post-endotoxin serum, TPA, 4 NQO, hormones and acetamide have been shown to induce maturation in experimental systems. This area of research is presently gaining considerable impetus.     

Oncogenes and their involvement in chronic myelogenous leukemia

This review highlights recent developments in the oncogene field relating to the molecular biology of chronic myelogenous leukemia (CML). At least 90% of patients diagnosed with CML carry an abnormal chromosome within their tumor cells. This chromosome is known as the Philadelphia chromosome. It results in most cases from an exchange of genetic material between chromosomes 9 and 22. As a result of this exchange the cellular abl gene from chromosomes 9, which is related to a viral oncogene, becomes fused to a region of chromsome 22 called the breakpoint cluster region (bcr). The hybrid bcr-abl gene is believed to play an important role in the disease process. The product of the fused bcr and abl genes is a 210,000 mol. wt. protein termed P210^bcr-abl. It has an associated protein kinase activity that phosphorylates tyrosine residues. Tyrosine protein kinases are thought to play an important role in the formation of tumors by rapidly acting RNA tumor viruses such as Abelson mouse leukemia virus. This virus has acquired part of the cellular abl gene from the mouse genome; viral infected tumor cells express a hybrid protein called P120^gag-abl, a tyrosine kinase believed to be responsible for the tumor phenotype. Similarly, P210^bcr-abl may play a key role in maintaining the tumor properties of leukemic cells of the CML patient.     

Genetics of cancer predisposition and progression

Summary The development of human cancer is a multistep process that entails a progressively more malignant phenotype through the evolution of cellular subsets with increasing numbers of genetic alterations. Here we review the molecular genetics of human cancer predisposition and progression and describe paradigmatic cancer types and cancer syndromes. We also briefly consider the future impact of molecular biology on cancer diagnosis and treatment.Abbreviations APC adenomatous polyposis coli - BWS Beckwith-Wiedemann syndrome - DCC deletion in colorectal cancer - EGFR epidermal growth factor receptor - FAP familial adenomatous polyposis - IGF insulin-like growth factor - LOH loss of heterozygosity - MEN multiple endocrine neoplasia - NF neurofibromatosis - NSCLC non-small-cell lung cancer - RCC renal-cell carcinoma - SCLC small-cell lung cancer - VHL von Hippel-Lindau syndrome - WAGR Wilms' tumor, aniridia, genitourinary anomalies, mental retardation syndrome - WT Wilms' tumor - ZF zinc finger     

Inhibition of epidermal growth factor receptor-overexpressing cancer cells by camptothecin, 20-(N,N-diethyl) glycinate

The epidermal growth factor receptor (EGFR) represents a prognostic marker for short survival of patients and therapy resistance of tumors. Despite clinical usefulness of EGFR tyrosine kinase inhibitors, resistance can develop. Therefore, there is an urgent need for novel EGFR inhibitors. Camptothecins have been characterized as inhibitors of DNA topoisomerase I (TOP1), although a correlation between TOP1 expression and activity is not well established in clinical biopsies. Hence, other targets may also be relevant. By molecular docking, we found that camptothecin 20-N,N-glycinate (CPTg) and camptothecin (CPT) bind to the same pharmacophore at EGFR as erlotinib, albeit to partly different amino acids. To validate the in silico results, CPT and CPTg were evaluated for their cytotoxic activity and downstream signaling mechanisms in U87MG glioblastoma cell lines transduced with different expression vectors for EGFR. All transduced cell lines were more susceptible to CPTg or CPT than the non-transduced cells, indicating a preferential activity towards EGFR-expressing tumor cells. Microarray-based mRNA hybridizations were performed in treated a non-treated cell lines. Subsets of genes were commonly regulated between the cell lines. By pathway analyses, we ranked canonical pathways according to differential gene expression after drug treatment. The pathways for G2/M DNA damage checkpoint regulation, aryl hydrocarbon receptor signaling, and xenobiotic metabolism and endoplasmatic reticulum stress were top ranked. In conclusion, binding of CPTg and CPT to the erlotinib pharmacophore and preferential cytotoxicity towards EGFR-overexpressing cells indicate susceptibility towards erlotinib-resistant tumors. Multiple mechanisms may account for cytotoxicity of these camptothecins.     

前列腺癌与前列腺增生HER-2及C-myc基因mRNA表达的研究

目的 检测良性前列腺增生(BPH)与前列腺癌(PCa)组织标本HER-2及C-mvc mRNA相对值,探讨此值对PCa诊断的特异性意义.方法 通过实时荧光定量PCR检测63例PCa、37例BPH及3例正常前列腺组织HER-2及C-myc mRNA的表达,比较其在PCa与BPH中组织定量的差异.结果 相对于BPH,PCa HER-2及C-myc mRNA表达相对值分别为4.25±0.03,7.24±0.06,PCa HER-2及C-myc表达相对值较BPH高,差异有统计学意义(均为P<0.05).结论 实时荧光PCR定量检测HER-2及C-myc mRNA为PCa的诊断提供了重要的辅助指标.     

逆转录病毒载体介导HPV16 E6E7基因转化人胚食管纤维细胞的研究

目的 研究HPV16型病毒感染与食管癌发生的关系。方法 包装含有HPVl6E6E7基因重组逆转录病毒，以重组病毒感染人胚食管纤维细胞，在TPA协同下诱导SCID小鼠成瘤。结果 重组病毒感染人胚食管纤维细胞可以诱导SCID小鼠形成肉瘤，可以检测到E6E7基因的存在及表达，流式细胞仪检测从瘤组织培养出来的纤维细胞，确定为异倍体；但未能诱导人胚食管组织成瘤。结论 建立的重组逆转录病毒系统可以成功介导HPV16E6E7基因的转移，可以应用于HPV致瘤性研究。     

Parallel epigenetic and genetic changes in the pathogenesis of hepatitis virus-associated hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most frequent tumor types in the world, with short survival times and few treatment options. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major etiologic agents of HCC, although the associated mechanisms are incompletely understood. The available evidence suggests that both viruses promote tumorigenesis by up-regulating genes that promote hepatocellular growth and survival, and by down-regulating other genes that act as tumor suppressors and negative growth regulatory molecules. Significantly, a number of the pathways that are altered by these viruses are the same ones that accumulate genetic alterations during tumor progression. This suggests that the pathways that promote virus persistence and replication may also promote cell growth and survival. From the perspective of the virus, this promotes chronic infection, while from the perspective of the host, this promotes tumorigenesis.     

Oncogene proteins as biomarkers in the molecular epidemiology of occupational carcinogenesis

Summary The use of oncogene proteins as biomarkers offers a new approach to the molecular epidemiologic evaluation of occupational carcinogenesis. The ras oncogene-encoded p21 protein represents a prototype for this type of study, since it is known to be activated by common occupational carcinogens, is frequently found in human tumors of occupational concern, and, at least in certain instances, appears to be expressed relatively early in the disease process, allowing the possibility of early detection and intervention. Herein, we review our experience with the use of immunologic detection of p21 in cohorts with cancer or at risk for the development of cancer due to their occupational exposures. The results suggest that p21 (particularly when used with other oncoproteins and biomarkers such as PAH-DNA adducts) will indeed be a useful addition to the growing armamentarium of molecular epidemiologic biomarkers in the study of occupational carcinogenic mechanisms and in the detection and prevention of occupational cancers.This paper was delivered at the presentation of the Robert R. J. Hilker Award in Occupational Medicine, Chicago, Illinois, March 30, 1990     

温石棉改性前后对人胚肺细胞癌基因改变的比较

目的寻求一种适宜的石棉表面改性剂。方法利用斑点杂交和流式细胞技术观察柠檬酸铝、混合稀土或亚硒酸钠等３种化合物对温石棉致人胚肺（ＨＥＬ）细胞转化过程中ｃＨａｒａｓ癌基因和Ｐａｎｒａｓ小鼠抗体（Ｐ２１ｒａｓ）蛋白的影响。结果在温石棉染毒组，ｃＨａｒａｓ癌基因的转录水平及Ｐ２１ｒａｓ蛋白含量明显高于对照组。在上述３种化合物预处理的温石棉组，ＨＥＬ细胞ｃＨａｒａｓ癌基因的转录水平及Ｐ２１ｒａｓ蛋白含量均明显低于未处理温石棉组。结论用上述３种化合物预处理温石棉，有可能减轻温石棉对人类的致癌危害性。