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

Although oncogenes and tumor suppressor genes have been implicated in carcinogenesis and tumor progression, their relationship to the development of genomic instability has not been elucidated. To examine this role, we transfected oncogenes (polyomavirus middle [Py] and large T [MT and LT]) and adenovirus serotype 5 E1A) into two NIH 3T3-derived cell lines, EN/NIH 2-4 and EN/NIH 2-20. Both cell lines contain two stable integrants of a variant of the retrovirus vector pZipNeoSV(x)1 that has been modified by deletion of the enhancer elements from the long terminal repeats. DNA rearrangements activating the silent neomycin phosphotransferase gene (neo) present in these integrants were identified by selection of cells in the antibiotic G418. Whereas control-transfected EN/NIH cell lines do not yield G418-resistant subclones (GRSs), a fraction of oncogene-transfected EN/NIH 2-4 (8 of 19 Py MT, 5 of 17 Py LT, and 11 of 19 E1A) and 2-20 (7 of 15 Py MT) cell lines gave rise to GRSs at differing frequencies (0.33 x 10(-6) to 46 x 10(-6) for line 2-4 versus 0.11 x 10(-6) to 1.3 x 10(-6) for line 2-20) independent of cell generation time. In contrast, a distinctly smaller fraction of mutant Py MT-transfected EN/NIH cell lines (1 of 10 MT23, 1 of 10 MT1015, and 0 of 10 MT59b) resulted in GRSs. Southern analysis of DNA from selected oncogene-transfected GRSs demonstrated genomic rearrangements of neo-containing cellular DNA that varied in type (amplification and/or novel fragments) and frequency depending on the specific oncogene and EN/NIH cell line used in transfection. Furthermore, only one of the two neo-containing genomic loci present in both EN/NIH cell lines appeared to be involved in these genomic events. In addition to effects related to the genomic locus, these observations support a role for oncogenes in the development of genetic changes associated with tumor progression.
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PMID:Oncogenes result in genomic alterations that activate a transcriptionally silent, dominantly selectable reporter gene (neo). 130 88

Hepatocyte growth factor (HGF) is a potent mitogen for primary hepatocytes. Therefore, we examined HGF as a possible autocrine growth factor in hepatocellular carcinoma (HCC). We introduced an albumin-HGF expression vector into Fao HCC cells and transgenic mice. Expression of the albumin-HGF vector in Fao HCC cells inhibited their growth in vitro. In vivo, FaoHGF cells produced tumors that averaged 10% of the sizes of G418-resistant controls when transplanted into nude mice. In contrast, hepatocytes from transgenic mice expressing HGF grew more rapidly than did those from normal siblings. Further, growth of eight additional HCC cell lines was inhibited by the addition of recombinant HGF. Finally, of 35 tumor cell lines surveyed, only 6 cell lines expressed HGF mRNA, and no HCC cell line expressed HGF. Although HGF stimulates normal hepatocytes, it is a negative growth regulator for HCC cells.
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PMID:Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells. 130 12

A retroviral vector, called pDAM3, containing the neomycin resistant gene and the antisense human c-myc gene fragment (the third exon and 3' flanking sequence) was constructed. pDAM3 was introduced into amphotropic packaging cells PA317 by the calcium phosphate precipitation method. Several G418-resistant PA317 clones were isolated. The virus titer of these cell lines was determined by infectivity of their culture fluid to NIH/3T3 cells. The highest titer obtained was 8 x 10(5) G418-resistant colony forming units/ml. Clonal and pooled G418-resistant PA317 colonies with high titers were expanded and analyzed by Southern blot for the presence of intact viral sequences. All cell lines were found to harbor the internal sequences of the pDAM3 vector without any rearrangement. Recombinant virus DAM3 infected human esophageal cancer cell line EC8712 efficiently. The DAM3-infected EC8712 (called EC-DAM3) was found to contain the full DAM3 sequence (4.8 kb) by Southern blot analysis. Antisense myc RNA expressed in the EC-DAM3 cell was detected by RNA hybridization. Further studies indicated that [3H]-thymidine incorporation in EC-DAM3 cells was reduced by 45% in average compared to that in untreated EC8712 cells. Growth rate of EC-DAM3 cells also decreased about 50%. DAM3-infected EC8712 cells lost their ability of forming tumor in nude mice. It thus appeared that the antisense myc gene introduced into EC8712 cells via retrovirus vector was capable of inhibiting cell proliferation and malignancy.
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PMID:Retrovirus mediated transfer of antisense human c-myc gene into human esophageal cancer cells suppressed cell proliferation and malignancy. 131 26

A pSV3neo-transfected rat ovarian cell line (SV-GC) was developed from a primary granulosa culture (GC) to study gap junctional intercellular communication (GJIC) during Simian virus 40 (SV40) transformation. SV-GC expressed SV40 large T-antigen (T-ag), grew indefinitely in culture without luteinization, was anchorage independent, and formed tumors in nude mice. Ultrastructural analysis identified abundant gap junctional membrane and suggested that SV-GC was arrested at an early stage of differentiation. Functional GJIC, measured by a dye transfer technique (gap FRAP), was comparable to that observed in normal granulosa cells, suggesting that the expression of T-ag alone was insufficient to reduce GJIC. However, there was approximately a 50% loss in the rate of GJIC in the nude mouse SV-GC-tumor derived and G418 selected cell line (T-SV-GC). SV-GC----T-SV-GC also resulted in a transition from migration of cells as an epithelial sheet to the dissociation of individual fibroblastoid cells. Tumor cell detachment was also seen in migrating malignant human (A2780 and 547) and rat (DC3) ovarian cell lines. Co-culture combinations of normal (GC)----transformed (SV-GC)----tumor-derived (T-SV-GC) cells indicated that the rate of heterologous GJIC was characteristic of the least communicating partner. Taken together, these data suggested that SV-GC----T-SV-GC represented progression toward metastasis with concomitant reduction of GJIC and adhesiveness. These sequentially derived cell lines may be a useful in vitro model system for studies focusing on the mechanism involved in the detachment of cells during the progression of ovarian cancer.
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PMID:Cell-to-cell communication competence in simian virus 40-transfected rat ovarian cells is reduced following tumor selection. 132 6

P-glycoprotein (Pgp), encoded by the MDR1 gene, is an active efflux pump for many structurally diverse lipophilic compounds. Cellular expression of Pgp results in multidrug resistance (MDR) in vitro and is believed to be a clinically relevant mechanism for tumor resistance to chemotherapy. We have developed a mouse monoclonal antibody, UIC2, that recognizes an extracellular epitope of human Pgp. UIC2 inhibited the efflux of Pgp substrates from MDR cells and significantly increased the cytotoxicity of Pgp-transported drugs, under the conditions where no effect was detectable with other anti-Pgp antibodies. Potentiation of cytotoxicity by UIC2 was observed with all the tested drugs associated with MDR (vinblastine, vincristine, colchicine, taxol, doxorubicin, etoposide, actinomycin D, puromycin, and gramicidin D) but not with any of the drugs to which MDR cells are not cross-resistant (methotrexate, 5-fluorouracil, cis-platinum, G418, and gentamicin). The inhibitory effect of UIC2 in vitro was as strong as that of verapamil (a widely used Pgp inhibitor) at its highest clinically achievable concentrations. Our results suggest that UIC2 or its derivatives provide an alternative or supplement to chemical agents for the reversal of MDR in clinical cancer.
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PMID:Efficient inhibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody. 135 77

A new bone cell line was established by transfecting normal adult human osteoblast-like (hOB) cells, derived from a 68-year-old woman, with the plasmid pSV3 neo. The plasmid included coding sequences and promotors for the large and small T antigens of the SV40 virus as well as resistance to the antibiotics neomycin and G418. A single antibiotic-resistant colony was located and cloned. Large tumor antigen production in the clonal cell line was confirmed by indirect immunofluorescence study. Treatment with 1,25-dihydroxy-vitamin D3 increased steady-state concentrations of protein and mRNA for osteocalcin and for alkaline phosphatase. Northern blot analyses also demonstrated the presence of mRNAs for alpha(I)-procollagen, osteopontin 1a, transforming growth factor beta, and interleukin-1 beta. The plasma membrane calcium pump and osteonectin were identified by immunocytochemical analysis. These cells produced a matrix that mineralized when beta-glycerophosphate was added to their cultures. As assessed by functional receptor assays, both estrogen and androgen receptors were present and functional, although at low concentrations. Treatment with parathyroid hormone did not stimulate adenylate cyclase activity. Thus, these cells are a well-differentiated, steroid-responsive clonal cell line that closely approximates the phenotype of the mature osteoblast. They should serve as an excellent model for the study of osteoblast biology.
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PMID:Development and characterization of a rapidly proliferating, well-differentiated cell line derived from normal adult human osteoblast-like cells transfected with SV40 large T antigen. 137 29

The present study reports on the use of gene transfer by vector DNA in the generation of hybrid hybridoma, the quadroma secreting the hybrid bispecific antibody. A quadroma B72.3neo/OKT3gpt was simply derived from the fusion of two hybridoma cell lines, B72.3 and OKT3, tagged with vector DNA mpSV2neo and mpSV2gpt, respectively, and selected in the media containing both G418 and mycophenolic acid. The hybrid bispecific antibody B72.3/OKT3 was purified from the quadroma ascites by the use of hydroxylapatite column on high-pressure liquid chromatography. This bispecific antibody contained one binding site for the TAG72 antigen on OVCAR3 tumor cells and the other binding site for the CD3 molecule on human T cells. It was able to target human T lymphocytes to significantly lyse the human ovarian cancer cells and may therefore be useful in immunotherapy of cancer.
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PMID:Production of hybrid bispecific antibody recognizing human colorectal carcinoma and CD3 antigen. 138 10

We have produced a high-affinity chimeric anti-colorectal carcinoma antibody, ccM4, chimerized in both heavy and light chains by the construction of two expression vectors, the chimeric heavy-chain expression vector mpSV2neo-EP1-Vm4Cr1 and chimeric light-chain vector mpSV2gpt-EP1-VKCK. These vectors contained the neo or gpt gene as a selection marker, the murine immunoglobulin promoter and enhancer (EP1), the genomic DNA fragments of human immunoglobulin constant region (CK and C gamma 1), and murine cDNA fragments of VH and VK region amplified and cloned directly from the B72.3 hybridoma RNA by the polymer chain reaction technique. These two vector DNAs were sequentially transfected into the SP2/0Ag14 cell line. Transfectants were selected in media containing both G418 and mycophenolic acid. The ccM4 antibody was purified from transfectant supernatants with positive binding reactivity for the TAG72 antigen on a protein A column. We demonstrated that ccM4 antibody retained the same high binding reactivity for the TAG72 antigen as its counterpart, the high-affinity chimeric heavy-chain cB72.3m4 antibody. The ccM4 antibody bound specifically to human colon cancer cells, displayed biodistribution patterns similar to cB72.3m4 antibody, and mediated effective antibody-dependent cellular cytotoxicity to human OVCAR3 tumor cells. Therefore, the high-affinity chimeric ccM4 antibody should be useful in cancer immunotherapy.
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PMID:Construction and characterization of a high-affinity chimeric anti-colorectal carcinoma antibody ccM4. 147 71

Lymphocytes have a finite and predictable proliferative life span in culture similar to that observed in fibroblasts. In general, the senescence of human fibroblasts is inevitable and irreversible, but their proliferative life span can be extended by certain DNA tumor virus oncogenes, such as the large T antigen of the SV40 virus. Here, we show that human T lymphocytes (HTL) can be stably transfected with SV40 large T and that expression of T antigen extended the life span of T cell cultures. PHA-stimulated HTL were transfected with pSV3neo, an expression vector containing the SV40 early region and the neomycin resistance gene. Transfectants were selected for neomycin (G418) resistance. Control HTL, either mock transfected or transfected with pSV2neo (containing the neomycin resistance gene only), ceased proliferation after about 17 population doublings. In contrast, HTL transfected with pSV3neo underwent more than 170 doublings. pSV3neo-transfected cells expressed SV40 large T RNA, detectable by in situ hybridization, and SV40 T antigen, detectable by immunofluorescence. Greater than 95% of the transfected cells were CD4 positive. These results clearly show that SV40 large T enables HTL to escape senescence. Transfection with SV40 large T may be a valuable method for obtaining long term human T cell lines for studies of both aging and immunology.
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PMID:Extension of lifespan of human T lymphocytes by transfection with SV40 large T antigen. 154 79

The mechanism by which normal human prostate cells develop into prostatic carcinoma cells is not presently known. In the present study we have tested the hypothesis that specific prostatic carcinomas develop as a consequence of activation of a cellular gene(s) with transforming and tumorigenic potential. To test this possibility, high molecular weight DNA was extracted from the human prostatic carcinoma cell line, LNCaP, and cotransfected with a dominant acting neomycin resistance gene, pSV2-neo, into a subclone of Fischer rat embryo fibroblast (CREF) cells, CREF-Trans 6, and NIH-3T3 cells. Cells were selected for growth in G418 and pooled resistant colonies, which were morphologically normal, were injected subcutaneously into athymic nude mice. Tumors developed in several of the animals inoculated with LNCaP DNA-transfected CREF-Trans 6 cells and they were established in monolayer culture. In contrast, no tumors developed in nude mice injected with untransfected CREF-Trans 6 cells, pSV2-neo transfected CREF-Trans 6 cells or LNCaP plus pSV2-neo DNA-transfected NIH-3T3 cells. DNA from the first cycle tumor-derived CREF-Trans 6 cell lines, which were morphologically transformed in monolayer culture, was cotransfected with pSV2-neo a second time into CREF-Trans 6 cells and transfected cells, which were still morphologically normal, were injected into nude mice. Tumors developed in animals and they were again established in tissue culture. Secondary transfectants isolated from animals were morphologically transformed and grew with high efficiency in agar. Both primary and secondary LNCaP-transfected-nude mouse tumor derived-CREF-Trans 6 cells contained human repetitive (Alu) sequences. Although the pattern of Alu integration in the tumor derived CREF-Trans 6 cells were different for different tumors, both primary and secondary tumors contained a single apparently common-sized Alu fragment. The present study indicates that the human prostatic carcinoma cell line, LNCaP, contains a dominant-acting tumor-inducing oncogene which does not induce morphological transformation of CREF-Trans 6 or NIH-3T3 cells in monolayer culture. In addition, the CREF-Trans 6 cell line can detect this tumor-inducing gene function, whereas this activity is not observed in DNA-transfected NIH-3T3 cells.
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PMID:Transfer of a dominant-acting tumor-inducing oncogene from human prostatic carcinoma cells to cloned rat embryo fibroblast cells by DNA-transfection. 158 May 47


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