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

The effect of fetal calf serum (FCS) on in vitro invasion by rat ascites hepatoma cells (AH130) was studied by using the in vitro invasion assay. Although the coculture of the highly invasive clone (MM1) of AH130 cells and the mesothelial cell layer or endothelial cell layer in modified minimum essential medium supplemented with 10% FCS resulted in extensive penetration of the layer by the tumor cells, the omission of FCS resulted in an almost complete elimination of the in vitro invasion. The in vitro invasiveness by human small cell lung cancer cells (OC10) was also remarkably reduced by the omission of FCS from the assay medium, suggesting a requirement of serum for the in vitro tumor cell invasion. When 10% FCS was added to the medium 2 h after the tumor cell seeding in FCS-free invasion assay system, penetration by MM1 cells was observed within an hour. This rate of penetration was almost the same as that when 10% FCS was added at the time of tumor cell seeding. FCS was also required for the penetration of a mesothelial cell monolayer by MM1 cells in a defined growth medium (SFM-101), in which MM1 cells were well maintained. The invasion-inducing activity appears to be independent of the growth-stimulating activity in serum.
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PMID:Serum requirement for in vitro invasion by tumor cells. 190 95

The CA 50 levels in serum samples from 440 patients were estimated using a dissociated enhanced lanthanide immunofluorimetric assay. The distribution was similar to CA 50-RIA assays. Raised levels (greater than 14 U/ml) were present in 95% pancreatic cancer, 68% hepatoma, 54% advanced colorectal cancer, 58% advanced breast cancer and 48% lung cancer. High values were observed in adenocarcinoma of the lung, and were related to tumour mass in small cell lung cancer. CA 50 is independent of CEA. The marker is of considerable potential in pancreatic cancer where the majority of patients express the Can 50 Ag.
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PMID:An evaluation of serum CA 50 levels in cancer using a time-resolved fluoroimmunoassay. 317 5

The purpose of this investigation was to examine factors which regulate the reprogramming of gene expression in tumors responsible for resistance to tiazofurin. To study the resistance phenomenon drug-induced tumor lines were selected and examined for the mechanism of resistance. A comparison of the biochemical expression of resistance to tiazofurin in drug-induced resistant lines of hepatoma 3924A, leukemias L1210 and P388 revealed that the 3 lines expressed similar genetic alterations related to reduced TAD content, decreased NAD pyrophosphorylase activity and increased synthesis of guanylates from salvaging preformed guanine indicating that these 3 factors play an important role in the resistance to tiazofurin. Resistance was stable in the leukemia lines and did not require drug to maintain resistance. Hepatoma 3924A resistant line reverted to sensitive state in the absence of drug selection pressure. NAD pyrophosphorylase activity was substantially deleted in the tiazofurin resistant leukemia lines, but was only significantly decreased in the hepatoma resistant line. Extensive biochemical alterations including enhanced activity of IMP dehydrogenase, increased inosinate and guanylate pools, and reduced uptake of tiazofurin were found in the hepatoma line resistant to tiazofurin. To examine the applicability of these results to naturally sensitive and spontaneously resistant tumors, murine tumors were examined. In murine tumors, TAD accumulation, ratios of enzyme activities responsible for the synthesis and degradation of TAD, and the ratios of perturbation of inosinate and guanylate pools following tiazofurin challenge demonstrated significant correlation with the sensitive or resistant nature of the tumors. To extrapolate these observations to human tumor systems, cytotoxicity of tiazofurin and its metabolic effects were compared in 6 human lung cancer cell lines derived from cancer patients with small cell lung cancer (4 lines) and lung adenocarcinoma (2 lines). Cell lines exhibiting greater sensitivity to tiazofurin accumulated significantly larger amounts of TAD and showed significant reduction of guanylate pools following tiazofurin incubation. The activity of the enzyme responsible for the formation of TAD, NAD pyrophosphorylase, did not correlate with responsiveness to tiazofurin but the enzyme which hydrolyzes TAD, TADase, correlated positively with the status of resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biochemical mechanisms of resistance to tiazofurin. 383 25

Epirubicin is the 4' epimer of the anthracycline antibiotic doxorubicin, and has been used alone or in combination with other cytotoxic agents in the treatment of a variety of malignancies. Comparative and noncomparative clinical trials have demonstrated that regimens containing conventional doses of epirubicin achieved equivalent objective response rates and overall median survival as similar doxorubicin-containing regimens in the treatment of advanced and early breast cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), non-Hodgkin's lymphoma, ovarian cancer, gastric cancer and nonresectable primary hepatocellular carcinoma. Recently, dose-intensive regimens of epirubicin have achieved high response rates in a number of malignancies including early and advanced breast cancer and lung cancer. The major acute dose-limiting toxicity of anthracyclines is myelosuppression. In vitro and clinical studies have shown that, at equimolar doses, epirubicin is less myelotoxic than doxorubicin. The lower haematological toxicity of epirubicin, as well as the recent introduction of supportive measures such as colony-stimulating factors, has allowed dose-intensification of epirubicin-containing regimens, which is particularly significant because of the definite dose-response relationship of anthracyclines. Cardiotoxicity, which is manifested clinically as irreversible congestive heart failure and/or cardiomyopathy, is the most important chronic cumulative dose-limiting toxicity of anthracyclines. Epirubicin has a lower propensity to produce cardiotoxic effects than doxorubicin, and its recommended maximum cumulative dose is almost double that of doxorubicin, thus allowing for more treatment cycles and/or higher doses of epirubicin. In summary, dose-intensive epirubicin-containing regimens, which are feasible due to its lower myelosuppression and cardiotoxicity, have produced high response rates in early breast cancer, a potentially curable malignancy, as well as advanced breast, and lung cancers. Furthermore, there is evidence to suggest that improved response rates can improve quality of life in some clinical settings, but whether this leads to prolonged survival has not yet been determined. Recently implemented supportive measures such as colony-stimulating factors, prophylactic antimicrobials and peripheral blood stem cell support may help achieve other potential advantages of dose-intensive epirubicin-containing regimens such as reductions in morbidity and length of hospital admissions.
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PMID:Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. 768 69

Lonidamine is an antispermatogenic and anticancer drug that is believed to act by inhibition of energy metabolism. In this study, the effects of Lonidamine on the concentration of intracellular free Ca2+ of several tumor cell lines were assessed because of the important role that cytosolic Ca2+ plays in cell viability and proliferation. The presence of 300 microM Lonidamine resulted in large elevations of cytosolic Ca2+ (> 100 nM) in AS-30D rat ascites hepatoma cells and in cultured EMT6 murine mammary adenocarcinoma cells but had little effect on cultured NCI-H345 human small cell lung cancer cells. The apparent EC50 for Lonidamine was approximately 175 microM. The source of elevated cytosolic Ca2+ was primarily intracellular stores, and the effects of Lonidamine on Ca2+ efflux from these stores did not appear to be due to an ionophoretic action of this compound or to a decline in the level of cellular ATP. These results indicate that the Ca2+ homeostasis of certain lines of tumor cells is specifically altered by Lonidamine at concentrations known to affect cell proliferation.
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PMID:Non-ionophoretic elevation of intracellular Ca2+ by Lonidamine. 834 57

We evaluated the long-term outcome of 148 patients with small cell lung cancer (SCLC) who had been entered into clinical trials of chemotherapy with or without thoracic and prophylactic cranial irradiation (PCI) between 1981 and 1987. Eighteen patients (12%) survived for 2 or more years. With a minimum follow-up of 4.5 years, 10 of the 18 patients who remained disease-free at 2 years are currently alive and free of SCLC. Seven of these 10 patients currently function as they did before diagnosis. However, three suffer from central nervous system changes of varying degrees in severity which appeared 2-3 years after PCI. Eight of the 18 patients who were disease-free at 2 years have died. Two died of isolated relapse in the brain at 3.6 and 4.2 years after initiation of chemotherapy. Five died of other malignancies while continuing their complete response to SCLC; two of non-small cell lung cancer, two of acute myelogenous leukemia, and one of hepatocellular carcinoma. Another patient died of an unrelated disease without any evidence of SCLC. A small but substantial proportion of patients who underwent intensive treatment will achieve long-term survival; however, these patients remain at higher risk for second cancers and late toxicities. Therefore, attention must be directed to defining the safest way to employ such treatment in the management of SCLC.
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PMID:Mortality and morbidity in two-year disease-free survivors of small cell lung cancer after treatment with combination chemotherapy with or without irradiation. 839 70

The daphnane-type diterpene gnidimacrin, isolated from the root of the Chinese plant, Stellera chamaejasme L., was found to strongly inhibit cell growth of human leukemias, stomach cancers and non-small cell lung cancers in vitro at concentrations of 10(-9) to 10(-10) M. On the other hand, even at 10(-6) to 10(-5) M, the small cell lung cancer cell line H69 and the hepatoma cell line HLE were refractory to gnidimacrin. The agent showed significant antitumor activity against murine leukemias and solid tumors in an in vivo system. In K562, a sensitive human leukemia cell line, gnidimacrin induced blebbing of the cell surface, which was completely inhibited by staurosporine at concentrations above 10(-8) M, and arrested the cell cycle transiently to G2 and finally the G1 phase at growth-inhibitory concentrations. It inhibited phorbol-12,13-dibutyrate(PDBu) binding to K562 cells and directly stimulated protein kinase C (PKC) activity in the cells in a dose-dependent manner (3-100 nM). Although activation of PKC isolated from refractory H69 cells was observed only with 100 nM gnidimacrin, the degree of activation was lower than that produced by 3 nM in K562 cells. Our results suggest that gnidimacrin acts as a PKC activator for tumor cells and that this mechanism may be responsible for its antitumor activity.
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PMID:Antitumor activity of daphnane-type diterpene gnidimacrin isolated from Stellera chamaejasme L. 860 23

Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibit resistance to the normal feedback effects of glucocorticoids on proopiomelanocortin (POMC) gene expression. This glucocorticoid resistance is typically complete, although some tumors show only relative glucocorticoid resistance in the clinical setting. The molecular mechanisms responsible for these clinical pathophysiologic observations are unknown, but might include glucocorticoid receptor defects or aberrant expression of enzymes or transporters that exclude glucocorticoids from access to their intracellular receptors. We examined whether ACTH-producing non-pituitary tumor cells might express 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the principal 'gatekeeper' enzyme known to metabolize glucocorticoids. 11Beta-HSD mRNA and enzyme activity were assessed in DMS-79 cells, a line derived from an ACTH-producing small cell lung cancer. RT-PCR studies showed expression of mRNA encoding 11beta-HSD2 but not 11beta-HSD1 in DMS-79 cells. Control human fibroblasts expressed predominantly 11beta-HSD1 but also had detectable 11beta-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11beta-HSD2 mRNA. Whole cell assays in DMS-79 cells revealed 11beta-HSD activity with a Km for cortisol of 26.1 +/- 9.0 nM and Vmax of 57.0 +/- 5.9 pmol/h/mg protein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11beta-HSD activity with a Km for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibited to 7% of baseline by addition of 10 microM glycyrrhetinic acid. Dexamethasone (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11beta-HSD2. While DMS-79 cells harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors.
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PMID:Expression of 11beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer. 988 91

Chemotherapy with cytostatic and cytotoxic drugs is the main treatment modality for disseminated cancer. However, despite initial clinical responses seen in certain histotypes, such as small cell lung cancer, relapses mostly occur with chemoresistant phenotypes. In order to prolong the relapse-free period, a combination of chemo- and immunotherapy might offer a new treatment strategy. Here, we have tested our hypothesis that complement activation, induced by monoclonal antibodies, in combination with cytostatic drugs may result in additive cytotoxicity in vitro. Doxorubicin, cisplatinum and etoposide were tested in combination with human complement and a murine monoclonal antibody (MAb F12) directed against the tumor-associated ganglioside antigen fucosyl GM1 on a rat hepatoma (H4-II-E) cell line which was used as tumor model. Using the MTT assay to measure cell survival, supra-additive (i.e. synergistic) cytotoxic effects were seen with each of the cytostatic drugs, the strongest being observed with doxorubicin. These results show promise for further research exploring possible prognostically favorable interactions between cytostatic drugs and monoclonal antibodies in the treatment of cancer.
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PMID:Supra-additive cytotoxic effects of a combination of cytostatic drugs and antibody-induced complement activation on tumor cells in vitro. 1112 82

Small cell lung cancer (SCLC) is an aggressive cancer, and most patients present with cancer already spread beyond the lung. The receptor tyrosine kinase (RTK) c-MET has been implicated in various solid tumors, including SCLC, and is involved in mediating tumorigenesis, cell motility, scattering, invasion and metastasis. Mutations of c-Met have been described in renal papillary carcinoma and gastrointestinal cancers including hepatocellular carcinoma. The sequence of c-MET was examined for possible mutations in the 10 SCLC cell lines and 32 paired-SCLC/normal tissues. Novel c-MET alterations were identified among 3 of 10 separate SCLC cell lines and in 4 of 32 SCLC tumor tissue samples. These include two different c-MET missense mutations in the juxtamembrane (JM) domain (R988C found in NCI-H69 and H249 cell lines; and T1010I in SCLC tumor sample T31). Also, there are one Sema domain missense mutation (E168D in SCLC tumor sample T5), two-base-pair insertional mutations (IVS13- (52-53)insCT in both SCLC tumor samples T26 and T27) within the pre-JM intron 13, as well as an alternative transcript involving exon 10 (H128 cell line). c-MET receptors are expressed at various levels among the 10 SCLC cell lines studied (high expression: H69, H345, H510, and H526; medium-expression: H128 and H146; and low/no-expression: H82, H209, H249, and H446). The level of c-MET expression does not have any apparent correlation with presence or absence of mutations of c-MET in the cell lines. We show that the two identified JM mutations (R988C and T1010I), when introduced into the interleukin-3 (IL-3)-dependent BaF3 cell line, regulated cell proliferation resulting in a small but significant growth factor independence. When introduced into a SCLC cell line (H446, with minimal endogenous wild-type c-MET expression), the JM mutations also regulated cell morphology and adhesion, as well as causing enhanced tumorigenicity by both increases in focus-formation and soft-agar colony-formation assays. Both of the JM mutations also increased cell motility and migration evident in wound healing assay and time-lapse video-microscopy speed analysis. The JM mutations also altered the c-MET RTK signaling, resulting in preferentially increased constitutive tyrosine phosphorylation of various cellular proteins, including the key focal adhesion protein paxillin on tyrosine residue Y31 (first CRKL-binding site), correlating with increased motility. These results suggest a novel and unique role of the JM domain in c-MET signaling in SCLC with significant implications in cytoskeletal functions and metastatic potential. The novel JM gain-of-function somatic mutations described are the first to be reported in SCLC, and may be associated with a more aggressive phenotype. It would now be useful to study the inhibition of c-MET as a therapeutic target against SCLC.
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PMID:c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. 1455 14


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