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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenic activation of ras results in changes in the transcription of several genes leading to uncontrolled cell growth. In this paper, we demonstrate that transformation of fibroblast cells by the ras oncogene leads to transcriptional repression of the smooth muscle alpha-actin promoter. Transient transfection analysis of plasmids containing the 5' upstream region of the human alpha-actin gene fused to human growth hormone or bacterial chloramphenicol acetyltransferase coding sequences into Rat-2 and ras-transformed Rat-2 (HO6) cells indicates that alpha-actin promoter is repressed in ras-transformed cells. In addition, stable rat fibroblast cell lines expressing human growth hormone or beta-galactosidase under the control of alpha-actin promoter exhibit repressed reporter gene activity following transformation by the ras oncogene. alpha-Actin promoter-driven beta-galactosidase activity is derepressed in revertants of ras-transformed stable cell lines. This revertant cell line expresses elevated levels of ras p21 protein and is resistant to retransformation by Ki and Ha-ras oncogenes. The revertant may have either a defective target protein whose activity is essential for the transforming activity of ras or an activated tumor suppressor gene which can suppress the activity of ras. These results indicate that smooth muscle alpha-actin promoter activity is a sensitive marker to follow phenotypic changes following transformation by ras and subsequent reversion. The advantages of this alpha-actin promoter-reporter gene assay system to screen for drugs that inhibit the transforming activity of ras, either directly or indirectly, are discussed.
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PMID:Regulation of smooth muscle alpha-actin promoter in ras-transformed cells: usefulness for setting up reporter gene-based assay system for drug screening. 145 76

Phorbol ester tumor promoters activate gene transcription by regulating both the synthesis and posttranslational modification of the activator protein 1 (AP-1) transcription factor, c-Jun and JunB are components of the mammalian AP-1 complex. Here we demonstrate that in U-937 human leukemic cells, phorbol esters stimulate the phosphorylation of the amino terminus of human c-Jun (JUN) but not human JunB (JUNB). Mutational analysis indicates that serine-63 and -73, which reside within the putative regulatory domain of JUN, are required for both constitutive and phorbol 12-myristate 13-acetate-inducible N-terminal JUN phosphorylation. To determine the functional role of this N-terminal phosphorylation, we prepared several chimeric proteins containing the N-terminal 84 amino acids (positions 5-89) of human JUN or murine JUNB fused to the yeast GAL4 DNA-binding domain. This region was found to be sufficient for the phorbol ester-inducible transcriptional activity of JUN, but not JUNB. This induction was abolished by the mutation of serine-63 and -73 to leucine residues. Thus, we propose that phorbol esters enhance the trans-activation potential of JUN, but not JUNB, by the phosphorylation of the N-terminal regulatory domain of JUN.
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PMID:Phorbol ester-induced amino-terminal phosphorylation of human JUN but not JUNB regulates transcriptional activation. 149 19

Following v-Ha-ras transfection of nonmetastatic dimethylbenz(( a ))anthracene-induced rat mammary cancer (RMC1) cells, occasional transfectants were isolated that acquired high metastatic ability. High metastatic ability is not a simple process regulated by v-Ha-ras p21 levels alone in these v-Ha-ras transfectants but involves the development of cytogenetic changes. If such cytogenetic changes involve only gain in gene expression, then all hybrids formed by fusing highly metastatic v-Ha-ras RMC1 transfectants with the parental nonmetastatic RMC1 should be highly metastatic. If loss of a metastatic suppressor gene(s) is also involved, then such hybrids should be nonmetastatic since chromosomes from the nonmetastatic parental cells should supply the suppressor function. To test this possibility, a highly metastatic cloned v-Ha-ras transfectant was fused with the nonmetastatic parental RMC1 cells. Five hybrid clones were isolated that conserved the chromosomes from their parental cells. When these hybrid clones were injected into animals, primary tumors developed with the same tumor-doubling time as that of the highly metastatic parental v-Ha-ras transfectant (i.e., approximately 2 days). High metastatic ability was, however, suppressed in these hybrid clones. All hybrid clones continued to express v-Ha-ras p21. Thus, suppression of metastatic ability in the hybrids can occur even in the presence of an elevated v-Ha-ras p21 level. This suggests that the acquisition of metastatic ability following v-Ha-ras transfection involves loss of metastasis suppressor gene function in rat mammary cancer cells.
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PMID:Genetic factors and suppression of metastatic ability of v-Ha-ras-transfected rat mammary cancer cells. 154 51

Tumour basement membrane (BM) is an extracellular matrix produced by tumour cells of epithelial origin. We examined the structure and function of the tumour BM of tumour tissues formed by Lewis lung carcinoma-derived cloned cell lines (P29, LM12-3 and LM60-D6 cells) with low, medium and high metastatic potentials, respectively. Immunohistochemical staining of major BM constituents laminin and type IV collagen demonstrated that all the cell lines produced and deposited these materials extracellularly in vivo. However, the continuity of the tumour BM composed of these materials was much greater in the higher metastatic LM12-3 and LM60-D6 tumours than in those with the low metastatic P29 tumour. Electron microscopic examination revealed that in the higher metastatic tumours, especially the LM60-D6 tumour, the tumour BM had a highly organized structure consisting of lamina densa and lamina rara. Parallel bilayers of BM and their fusion were often observed and tumour cells were in direct contact with the BM. In the vicinity of tumour blood vessels, similar interactions between the tumour BM and the vascular BM were observed, and the tumour cells rested on their own BM, the fused BM or the vascular BM. In contrast, in the low metastatic tumour in which the tumour BM was not clearly defined, this close contact between tumour cells and the vascular BM was not observed. In vitro studies showed that the higher metastatic cells adhered more firmly than the LMP cells to a subendothelial matrix. These results suggest that the adhesiveness of tumour cells to the vascular BM in vivo is correlated with their ability to form an integrated BM in vivo, and that this adhesiveness of the tumour cells may be mediated in part by the tumour BM via BM fusion.
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PMID:Morphological characteristics of tumours formed by Lewis lung carcinoma-derived cloned cell lines with different metastatic potentials: structural differences in their basement membranes formed in vivo. 154 5

In HeLa cells transcription of the c-jun gene is activated strongly and rapidly by ultraviolet (UV) irradiation and, to a somewhat lesser extent, by treatment with phorbol ester tumor promoters. In the same cells UV and phorbol esters only marginally enhance the abundance of RNA transcribed from the jun D gene and from the gene coding for the serum response factor (which in turn acts on the UV and phorbol ester response element of the c-fos gene). In contrast to c-jun, jun B transcription is induced more efficiently by phorbol ester than by UV irradiation, suggesting that the members of the jun family are differently regulated. The promoter of c-jun carries two enhancer elements resembling AP-1 binding sites: the jun1 UV response element (URE-71 TGACATCA -64) and the jun2 URE (-190 TTACCTCA-183). These elements act independently in the UV induced expression of c-jun. In the context of the complete c-jun promoter they seem not to be required for c-jun induction by phorbol esters. When fused to the Herpes simplex thymidine kinase promoter, however, the isolated elements mediate induction by both UV and phorbol esters. UV and phorbol ester treatment of cells increases the binding of transcription factors to both elements. Both elements bind factors different in modification or/and constitution from AP-1, the heterodimeric transcription factor composed of c-Fos and c-Jun that controls the activity of the UV and phorbol ester response element (-72 TGAGTCA-66) of the human collagenase gene.
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PMID:Ultraviolet-radiation induced c-jun gene transcription: two AP-1 like binding sites mediate the response. 156 Dec 39

The construction and expression of a chimeric gene encoding a mouse/human antibody to the human transferrin receptor fused to the gene for angiogenin, a human homolog of pancreatic RNase, are described. F(ab')2-like antibody-enzyme fusions were prepared by linking the gene for human angiogenin to a chimeric anti-transferrin receptor heavy chain gene. The antibody-enzyme fusion gene was introduced into a transfectoma that secretes the chimeric light chain of the same antibody, and cell lines were cloned that synthesize and secrete the antibody-enzyme fusion protein of the expected size at a concentration of 1-5 ng/ml. Culture supernatants from clones secreting the fusion protein caused inhibition of growth and protein synthesis of K562 cells that express the human transferrin receptor but not toward a non-human-derived cell line that lacks this receptor. Whereas excess antibody to the same receptor did not itself inhibit protein synthesis, it was able to completely prevent the protein synthesis inhibition caused by the fusion protein. These results indicate that the cytotoxicity is due to a transferrin receptor-mediated mechanism involving the angiogenin portion of the fusion protein and demonstrate the feasibility of constructing recombinant antibody-RNase molecules capable of killing tumor cells bearing the transferrin receptor. The significance of the acquired cytotoxicity of a mouse/human chimeric antibody linked to a human protein may bear importantly in human therapeutic strategies that use mouse antibodies linked to toxins from plants or bacteria to target tumor cells. It is expected that the humanization of immunotoxins will lead to less toxicity and immunogenicity than currently available reagents.
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PMID:Humanization of immunotoxins. 156 9

Identification of tumor suppressor gene loci in rodent cell culture systems has relied upon the use of somatic cell hybridization studies. Although normal rodent fibroblasts are capable of suppressing the tumorigenicity of a variety of tumor cells, the lack of complementation in tumor cell x tumor cell hybrids has left the possibility that a single tumor suppressor gene may be responsible for tumor suppression in a particular rodent cell culture system. Using this same approach, we found no evidence for complementation resulting in suppression of the transformed phenotype when three viral oncogene-transformed Syrian hamster embryo (SHE) cell lines and one spontaneously transformed baby hamster kidney (BHK) cell line were fused to benzo[a]pyrene-transformed SHE cells (BP6T-M3). However, v-src oncogene-transformed cell line (srcT) x BP6T-M3 hybrids did demonstrate limited suppression of the transformed phenotype, suggesting at least two complementing tumor suppressor genes in this system. We were able to confirm and extend this finding using another experimental approach with preneoplastic hamster cell lines that are immortal in culture but nontumorigenic in nude mice. We propose that fusion of these preneoplastic cells to various tumor cells may reveal tumor suppressor genes not evident in the tumor cell x tumor cell complementation studies. Subclones of two nontumorigenic, immortal hamster cell lines, 10W and DES4, displayed differing abilities to suppress BP6T-M3 cells in somatic cell hybrids, as quantitated by the ability of the hybrid cells to form colonies in soft agar. With a panel of preneoplastic hamster cell x BP6T-M3 hybrids, a distinct pattern of suppression or expression of the transformed phenotype was observed. Marked differences in this pattern were seen when the same 10W and DES4 subclones were fused to other hamster fibrosarcoma cell lines, indicating different tumor suppressing activities of multiple tumor suppressor genes. Analysis of this data suggests that as few as three or as many as six different tumor suppressor genes may be active in the Syrian hamster embryo cell culture system. Thus, this system may provide a useful model for identifying and studying the effects and regulation of a number of different tumor suppressor genes for fibrosarcomas.
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PMID:Detection of multiple tumor suppressor genes for Syrian hamster fibrosarcomas by somatic cell hybridization. 157 39

Active specific immunotherapy with irradiated allogeneic melanoma cells has been shown to enhance the humoral immune response in melanoma patients. An increased titer of melanoma-binding antibodies was demonstrated in sera of immunized patients. Lymph node cells and splenocytes isolated from an actively immunized melanoma patient were fused with the human-murine heteromyeloma cell lines SHMD-33, SPM4-0, and SBC-H20. A group of human anti-melanoma monoclonal antibodies (MABs) were generated from the SHMD-33 fusion. Isolated MABs (one IgG2, one IgA, and two IgM) have been stable in cultures for more than 12 months and have produced human immunoglobulins at 0.2-0.9 Ug/ml/day. As shown by solid phase radioimmunoassays, the MABs react with autologous tumor cells and allogeneic melanoma tumors, including the cell line that was used for immunotherapy. In immunocytochemical assays, all four MABs react with a number of melanoma tumor cell lines. The IgG2 and IgA MABs stained preferentially melanoma tumor cells. In contrast, the IgM MABs cross-reacted with a broad panel of tumor cells from colon, prostate, pancreas, lung, and other human tumors. The MABs appear to be directed to intracellular rather than membrane-associated antigens as shown by immunofluorescence assays on live and permeabilized cells. The IgG2 antibody recognizes a 70 kDa antigen in melanoma cell lysates by Western immunoblotting. The target antigens for the other MABs have not yet been defined. Stability in culture and strong binding to melanoma tumor cells provide the basis for evaluating the potential of these human MABs. The IgG2 MAB, in particular, may prove useful for diagnostic and therapeutic applications in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Generation of human IgG, IgA, and IgM anti-melanoma monoclonal antibodies utilizing lymphocytes of an actively immunized melanoma patient. 157 21

Transforming growth factor-alpha-Pseudomonas exotoxin-40 (TP40) is a recombinant fusion protein. TP40 consists of the entire human transforming growth factor-alpha (TGF alpha) protein fused to a 40,000 Da. segment of the Pseudomonas exotoxin A protein. TP40 is a bifunctional molecule that possesses the epidermal growth factor (EGF) receptor binding properties of TGF alpha and the cell killing properties of Pseudomonas exotoxin A. These properties make TP40 a selective cytotoxic agent that kills EGF receptor bearing cells. TP40 has been shown to effectively kill human tumor cell lines that possess EGF receptors in vitro and in nude mice. In the present study, TP40 was tested against tumors taken directly from patients and grown in a soft agar human tumor cloning system. A total of 107 patients' tumors (taken from patients with tumors refractory to chemotherapy) were tested with a continuous exposure to 0.5-50 nM concentrations of the agent. TP40 exhibited a clear dose response effect against a wide variety of human solid tumor colony-forming units with greater than or equal to 84% of evaluable tumors responding at a drug concentration greater than or equal to 24 nM. When used as a continuous exposure, concentrations of TP40 as low as 5 nM demonstrated substantial in vitro activity. This activity included cytotoxicity against breast, colorectal, endometrial, head and neck, non small-cell lung, gastric, sarcoma, and pancreatic cancer tumor colony-forming units. Additional in vivo testing of this compound is warranted.
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PMID:Activity of a recombinant transforming growth factor-alpha-Pseudomonas exotoxin hybrid protein against primary human tumor colony-forming units. 160 49

Twenty-eight occipitocervical fusions using the onlay technique were performed in 27 patients ranging in age from 13 to 77 years (average age, 47.6 years). The indications for fusion included neurologic involvement from atlantoaxial instability associated with superior migration of the odontoid and destructive changes at the occiput-C1-C2 articulation, causing pain unrelieved by conservative treatment. Preoperative diagnoses included rheumatoid arthritis, congenital anomalies, posttraumatic, failed C1-C2 fusions, ankylosing spondylitis, and tumor. A standard posterior exposure of occiput-C1-C2 was used, and iliac crest bone graft was placed over the area to be fused. Postoperative immobilization consisted of skull tong traction, minerva jacket, and halo apparatus. There were no neurologic complications, two superficial wound infections, and minor difficulties with halo loosening. There was one perioperative death. Primary fusion was obtained in 89% of patients at an average of 12.8 weeks. Occipitocervical fusion by the onlay technique is safe, requires no internal fixation, and has a high success rate when compared with other methods of obtaining fusion in the occipitocervical region.
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PMID:Onlay technique for occipitocervical fusion. 161 38


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