Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that O-phospho-L-tyrosine (P-Tyr), a substrate for a wide range of PTPases, inhibits the growth of human renal cell carcinoma and human breast cancer cell lines and suppresses EGF-mediated EGFR tyrosine phosphorylation. We now show that P-Tyr inhibited the growth of the human hepatoma cell line HEPG2, and src transformed NIH3T3 cells, but did not inhibit the growth of human ovarian carcinoma SKOV-3 cells. Addition of exogenous P-Tyr inhibited the insulin triggered insulin receptor (IR) tyrosine phosphorylation in the HEPG2 cell line and the tyrosine phosphorylation of a variety of cellular proteins in src-transformed NIH3T3 cells. P-Tyr did not inhibit the tyrosine phosphorylation of gp185 erbB-2 in P-Tyr resistant SKOV-3 cells. Thus, inhibition of cell growth by P-tyr was associated with decreased tyrosine phosphorylation of cellular proteins.
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PMID:Association of inhibition of cell growth by O-phospho-L-tyrosine with decreased tyrosine phosphorylation. 860 80

Biologically targeted radiotherapy in clinical practice requires a molecule which has a relative specificity for tumour tissue--the missile--coupled to a radionuclide with appropriate physical characteristics--the warhead. When administered to a patient this combination should result in selective irradiation of the target tumour cells with relative sparing of normal tissues. Simple ions and small molecules which follow physiological pathways as either the natural substrates or analogues form the best examples of biological targeting. Clinically valuable results are seen with, for instance, iodine uptake by normal and malignant thyroid cells, incorporation of the calci-mimetic element strontium in areas of increased bone metabolism and accumulation of the catecholamine analogue meta-iodobenzylguanidine in neuroblastoma. The use of monoclonal antibodies as targeting vehicles has not proved to be a panacea, yet some patients with lymphoma, hepatoma and ovarian carcinoma have obtained benefit. Current clinical studies in targeted radiotherapy focus on the integration of radionuclide treatment with conventional treatments, and the optimization of such combined approaches. The development of modifications to offset the limitations inherent in the use of crude antibodies also offers an opportunity for improved clinical outcomes.
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PMID:The current status of targeted radiotherapy in clinical practice. 891 69

We have previously shown that adenoviral-mediated delivery of an anti-erbB-2 intracellular single-chain antibody (sFv) causes specific cytotoxicy in erbB-2-overexpressing ovarian carcinoma cells. Furthermore, intraperitoneal delivery of the anti-erbB-2 sFv enhances survival and reduces tumor burden in a xenograft model of human ovarian carcinoma in SCID mice. These findings have led to an RAC-approved Phase I clinical trial for patients with ovarian cancer. In this report, we show that expression of the anti-erbB-2 sFv could be readily detected in target tumor cells by in situ hybridization methodology. PCR analysis of DNA extracted from various murine tissues demonstrated that the anti-erbB-2 sFv remained localized to the peritoneum. Delivery of the sFv to the non-erbB-2-overexpressing REN mesothelial and Hep G2 hepatocellular carcinoma cell lines was not deleterious to either one, affirming the tumor specificity of this gene therapy strategy. In addition, histopathological analysis of various tissues showed that adenoviral-mediated delivery of the anti-erbB-2 sFv to immunocompetent mice with either primary exposure or previous vector challenge at different doses produced no abnormal changes when compared to untreated animals. These findings suggest that adenoviral-mediated delivery of the anti-erbB-2 sFv in a human context can be effectively assayed, is potentially free of vector-associated toxicity, and retains biologic utility based on tumor specificity.
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PMID:Transductional efficacy and safety of an intraperitoneally delivered adenovirus encoding an anti-erbB-2 intracellular single-chain antibody for ovarian cancer gene therapy. 906 38

Evidence for heightened capacity for signal transduction in rat hepatoma as well as in human breast and ovarian carcinoma cells as reflected by coordinate increases in PI kinase and PIP kinase in the PI phosphorylation sequence leading to the production of second messengers IP3 and DAG is shown. The linkage of signal transduction enzymes with malignant growth is also seen as MDA-MB- 435 human breast carcinoma or ovarian OVCAR-5 cells express their proliferative capacity in tissue culture in the log phase. In both cases, quercetin inhibit cell proliferation with a decline in PI kinase activity and IP3 levels preceding the growth inhibition seen with quercetin. The elevated steady state activities of PI and PIP kinase indicate a metabolic up-regulation in signal transduction capacity of cancer cells which is down-regulated by quercetin. Since the gain in function manifested in the over-expressed capacity for signal transduction confers selective growth advantage to cancer cells, increased activities of PI and PIP kinases may be considered as sensitive targets for cancer chemotherapy. The potential of quercetin as an interceptor of intracellular signal transduction mechanisms needs to be explored.
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PMID:Intracellular signalling: phosphatidylinositol lipid metabolism in cancer cells. 934 25

The presence of gonadotropin-releasing hormone (GnRH) binding sites in biopsy samples of human epithelial ovarian cancer and ovarian tumor cell lines as well as the demonstration of the inhibitory effects of GnRH analogues on the growth of these cells raised the possibility that GnRH is produced locally by ovarian cancer cells. In order to investigate an autocrine/paracrine regulatory mechanism in human carcinomas, we have studied the expression of GnRH and GnRHR mRNA in human ovarian epithelial cell lines (OVCAR-3 and SKOV-3), human choriocarcinoma cell line (JEG-3) and human hepatocarcinoma cell line (HepG 2). Using primers corresponding to published human GnRH and GnRHR cDNA sequences, predicted PCR products were obtained from these cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and confirmed by Southern hybridization. Sequencing analysis of GnRH PCR products showed that their sequences have 100% identity to the published human GnRH cDNA sequence. These results indicated that GnRH and GnRHR genes are expressed in all the cell lines tested in the present study, and strengthen the concept that GnRH may act as an autocrine regulator on the growth of cancer cells.
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PMID:Expression of the messenger RNA for gonadotropin-releasing hormone and its receptor in human cancer cell lines. 962

Catheter complications associated with intraperitoneal chemotherapy were evaluated in 171 patients (pts) with primary intra-abdominal malignancies. In 96 pts and 488 courses, single-use catheters (SUC) (3/G 14 Braun) were used between years 1990-1993. In 75 pts and 283 courses a semi-permanent subcutaneous implantable port and catheter system (SIPC) (T 2035/460 mm-F 14-76 Braun) was used between years 1993-1996. Cisplatin (60-75 mg/sqm), 5-fluorouracil (600 mg/sqm), calcium folinate (150 mg), etoposide (180 mg/sqm), mitoxantrone (12-15 mg/sqm) were given in various combinations and periods to patients with ovarian carcinoma (106 pts), gastrointestinal carcinoma (43 pts), hepatocellular carcinoma (17 pts) and mesothelioma (5 pts). The incidence of patients with complications was significantly higher in SUC (45%) than SIPC (23%) (p=0.001). Colon puncture (8.8%, p<0.0001) and subcutaneous leakage (3.7%, p<0.01) rate of the courses were significantly higher in SUC. Pain related to catheter complications (6%, p<0,0002), local infection (1.4%, p=0.02) and obstruction (1.4%, p=0.02) were significantly higher in SIPC. The most important local complications were intra-abdominal fibrosis and adhesions that were surgically documented in 90% of the ovarian cancer patients, and were more severe in patients with the SIPC system. The complication rate and the complication type of these two catheters were found to be significantly different in this retrospective analysis; in order to determine the real complication rate, safety, efficacy and overall acceptability of the catheters, a randomised trial is needed.
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PMID:Catheter complications associated with intraperitoneal chemotherapy. 964 Dec 30

Recognition, internalization, and subcellular trafficking of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates containing N-acylated galactosamine (GalN) or monoclonal OV-TL16 antibodies (Ab) have been investigated in human hepatocarcinoma HepG2 and ovarian carcinoma OVCAR-3 cells, respectively. The intrinsic fluorescence of fluorescein or adriamycin (ADR) attached to HPMA copolymers permitted us to follow the subcellular fate of HPMA copolymer conjugates by confocal fluorescence microscopy and fluorescence spectroscopy. The pattern of fluorescence during incubation of HPMA copolymer-ADR-GalN conjugate containing lysosomally degradable tetrapeptide (GFLG) side-chains with HepG2 cells was consistent with conjugate recognition, internalization, localization in lysosomes, followed by the release of ADR from the polymer chains and ultimately diffusion via the cytoplasm into the cell nuclei. A similar pattern was observed in OVCAR-3 cells for Ab targeted HPMA copolymer conjugates. To test our hypothesis that HPMA-copolymer-bound anticancer drugs will be inaccessible to the energy-driven P-glycoprotein efflux pump in multidrug resistant (MDR) cells, we have compared the internalization of the HPMA copolymer-ADR conjugates by sensitive (A2780) and ADR-resistant (A2780/AD) ovarian carcinoma cell lines. Preliminary data on relative retention of ADR in MDR (A2780/AD) cells indicate a higher intracellular ADR concentration after incubation with HPMA copolymer-ADR conjugate when compared to incubation with free (unbound) ADR.
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PMID:Targetable HPMA copolymer-adriamycin conjugates. Recognition, internalization, and subcellular fate. 974 11

We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant tumors including glioblastomas and hepatocellular carcinomas (HCCs) and in tumor preexisting conditions such as hepatitis C virus- and hepatitis B virus-induced liver cirrhosis. The expression of MAG was characterized using reverse transcription-PCR (RT-PCR), rapid amplification of cDNA ends PCR, RNA dot blotting, RNase protection assay, and Northern blot analysis. Rapid amplification of cDNA ends PCR yielded a 536-bp MAG fragment in HCC, macroregenerative liver nodules with dysplasia, and liver cirrhosis but not in normal liver or placenta. By RT-PCR, MAG expression was not found in 12 different normal tissues but found in 46 of 51 (90%) premalignant and malignant tissues of various sites. Embryonic liver and brain were positive for MAG expression together with tumors from the same organs, but the corresponding normal adult tissues were negative. By RNase protection assay, MAG mRNA was expressed in the HepG2 liver tumor cell line and in an ovarian carcinoma but not in normal liver. The estimated transcript size from Northern blot analysis was 8.8 kb. This novel gene may play a role in the progression of premalignant conditions and in the development of HCC and other cancers.
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PMID:Novel human malignancy-associated gene (MAG) expressed in various tumors and in some tumor preexisting conditions. 976 81

The activity of uridine kinase (ATP: uridine 5'-phosphotransferase; EC 2.7.1.48), the rate-limiting enzyme of the UMP salvage pathway, was measured in human ovaries and ovarian carcinomas, in a spectrum of six rat hepatomas of different growth rates and in eleven normal rat tissues of high and low cell renewal rates. In a standard isotopic method developed for the 100,000 x g fraction, uridine kinase activity was linear for 20 min and proportional with protein concentration over a range of 0.1 to 0.8 mg per 0.1 ml reaction mixture. The apparent Kms for uridine, ATP and Mg++ in normal rat liver were 5.0, 3.4 and 1.5 mM and in the rapidly growing hepatoma 3924A, 0.8, 2.1 and 1.1 mM, respectively. In normal control ACl/N and Buffalo strain rat livers, kinase activity ranged from 159 to 180 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, kinase activity increased to 1.5- to 2.6-fold, and in hepatomas of rapid growth rates, to 5.1- to 5.8-fold over that of the relevant control, normal livers. When hepatoma 3924A tissue culture cells were plated and expressed their proliferative program, kinase activity increased to 2.1-fold in early log phase. To further clarify the linkage between uridine kinase and cell replicating capacity, the enzyme activity was measured in rat organs of high and low cell renewal. The kinase activity in liver of adult male Wistar rats was 176 +/- 6 nmol/h/mg protein. Activities in thymus, spleen and bone marrow were 4.7-, 2.1-, and 1.8-fold, respectively, of rat liver values; in adipose tissue, the activities were low. The decay rates of uridine kinase were examined in rats injected with a high dose of cycloheximide, which inhibits protein biosynthesis by 90%. The t(1/2) of the kinase in rat bone marrow was 0.64 h, in rat liver longer than 6 h. In human ovary and ovarian carcinoma, the apparent Kms for uridine were 11.5 and 0.5 mM, respectively. In human ovary (n = 3), kinase activity was 38 nmol/hr/mg protein; in ovarian carcinoma (n = 6), the activity increased to 5- to 13-fold over that in ovary. The positive linkage of uridine kinase activity with proliferation and transformation is apparent in human ovarian carcinomas and in rat hepatomas of different growth rates. Therefore, the increased uridine kinase activity should be an interesting target for anticancer chemotherapy.
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PMID:Increased uridine kinase (ATP: uridine 5'-phosphotransferase; EC 2.7.1.48) activity in human and rat tumors. 992 63

This study examined the relationship between the expression of E-cadherin or beta-catenin in murine adenocarcinomas and their hematogenous metastatic propensity, assessed by both spontaneous and artificial lung metastasis. Seven different carcinomas, syngeneic to C3Hf/Kam mice were used: 4 mammary carcinomas (MCa-4, MCa-29, MCa-35, and MCa-K), ovarian carcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG. These tumors vary widely in their ability to spontaneously metastasize to the lung (from 0 to 100% metastatic incidence), and their cells greatly differ in their ability to form artificial lung nodules when injected i.v. Primary tumors in the leg were assessed for E-cadherin and beta-catenin expression by western blotting. The expression of both proteins showed wide variation among the tumors; however, the expression of E-cadherin correlated well with that of beta-catenin. There was significant inverse correlation between the expression of E-cadherin, as well as beta-catenin, and the incidence of both spontaneous and artificial lung metastases from these tumors. Spontaneous metastases of highly metastatic HCa-I and moderately metastatic MCa-35 were significantly lower in E-cadherin and beta-catenin expression than their corresponding primary tumors were. Thus, the propensity of murine carcinomas for hematogenous spread is highly related to E-cadherin and beta-catenin levels in primary tumors. The inverse correlation between the expression of these molecules and spontaneous and artificial metastases implies that tumor cells with low E-cadherin and beta-catenin content have increased ability to enter the vascular circulation at the primary tumor site and to colonize distant tissues.
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PMID:Low E-cadherin and beta-catenin expression correlates with increased spontaneous and artificial lung metastases of murine carcinomas. 1041 Nov 10


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