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Biomedical subjects

Christoph Herold

Publications and source records attributed to Christoph Herold.

At least 19 recordsLinked to original sources
PubMed2007

Apoptosis, proliferation and differentiation patterns are influenced by Zebularine and SAHA in pancreatic cancer models.

OBJECTIVE: Pancreatic cancer continues to be an urgent clinical problem. We used the novel DNA methyltransferase inhibitor Zebularine and the histone deacetylase inhibitor SAHA to investigate the epigenetic influence on viability and differentiation of the pancreatic cancer cell lines YAP C, DAN G and Panc-89 in vitro and in vivo. MATERIAL AND METHODS: Cell vitality, proliferation and expression of PDX-1, cytokeratin 7 and 20, chromogranin A, vimentin, bax and bcl-2 were determined on the protein and mRNA level in vitro and in a subcutaneous xenograft model. RESULTS: A time- and dose-dependent increase of apoptosis, paralleled by decreased proliferation, was observed after incubation with single agents or a combination therapy with lower concentrations. This was associated with up-regulation of pro-apoptotic bax and a phenotypic stabilization by the enhanced expression of cytokeratin 7. In vivo, growth of xenografts was delayed with the most pronounced effect in Panc-89 after 1 week of daily intraperitoneal injections of Zebularine paralleled with CK7 up-regulation and down-regulation of dedifferentiation markers. CONCLUSIONS: Epigenetic modulation via inhibition of DNA methyltransferase and histone deacetylase induces apoptosis in human pancreatic cancer cells in vitro and delays xenograft growth in vivo, which is associated with a morphological/molecular phenotypic stabilization. These compounds may therefore be suitable as adjunctive therapeutic agents in the treatment of pancreatic cancer.

Animals↗
PubMed2006

Gastrointestinal cancer - only a deregulation of stem cell differentiation? (Review).

Recent research on embryonic and adult stem cells questions the currently accepted models of multi-step carcinogenesis in solid cancer. Accordingly, differentiated epithelial cells are considered to be the main target for mutational steps, leading to a growth and survival advantage of malignantly transformed cells. In contrast, the stem cell model of carcinogenesis emphasizes the role of stem cells as the initiating structure for tumor development. Yet, it is unclear if tumors contain dysregulated (embryonic) stem cells or if tumors consist of differentiated adult cells that obtained a de-differentiated stem cell-like phenotype. Here, we review the current knowledge on the roles of stem cells in gastrointestinal cancer formation and the implication on future diagnostic and therapeutic strategies.

Cell Differentiation↗
PubMed2005

Improvement of quantitative testing of liver function in patients with chronic hepatitis C after installment of antiviral therapy.

AIM: To investigate if and to what extent antiviral therapy influenced a broad panel of quantitative testing of liver function (QTLF). METHODS: Fifty patients with chronic hepatitis C were either treated with interferon (n = 8), interferon/ribavirin (n = 19) or peg-interferon/ribavirin (n = 23). Quantitative testing of liver function, including aminopyrine breath test (ABT), galactose elimination capacity (GEC), sorbitol clearance (SCl) and indocyanine green clearance (ICG) was performed before and 3 mo after initiation of antiviral therapy. RESULTS: After 3 mo of antiviral treatment, 36 patients showed normal transaminases and were negative for HCV-RNA, 14 patients did not respond to therapy. ABT and GEC as parameters of microsomal and cytosolic liver function were reduced in all patients before therapy initiation and returned to normal values in the 36 therapy responders after 3 mo. Parameters of liver perfusion (SCl and ICG) were not affected by antiviral therapy. In the 14 non-responders, no changes in QTLF values were observed during the treatment period. CONCLUSION: ICG and SCl remained unaffected in patients with chronic hepatitis C, while ABT and GEC were significantly compromised. ABT and GEC normalized in responders to antiviral therapy. Early determination of ABT and GEC may differentiate responders from non-responders to antiviral treatment in hepatitis C.

Adult↗
PubMed2005

Different capabilities of morphological pattern formation and its association with the expression of differentiation markers in a xenograft model of human pancreatic cancer cell lines.

AIMS: New concepts of tumorigenesis favor an unregulated process recapitulating different stages of embryogenic development with dysregulation of transition states. The aim of our study was to investigate the possibility of differentiation pathways of human pancreatic cancer cell lines in vivo. MATERIAL AND METHODS: Different human pancreatic cancer cell lines (YAPC, DAN-G, CAPAN-1, PANC-1 and MIA PaCa-2) were implanted subcutaneously (3 x 10(6) cells) for 28 days in nude mice. Xenotransplants were characterized with histochemistry (HE, PAS), immunohistochemistry (cytokeratin (CK)7, CK8, CK18, CK19, CK20, vimentin, chromogranin A (Chr-A), alpha1-antichymotrypsin (alpha1-chym), beta-catenin, laminin-5, pancreatic and duodenal homeobox gene 1 (pdx-1), sonic hedgehog protein (shh), Patched (ptc)), Western blotting and real-time PCR (CK7, CK8, CK20, Chr-A, pdx-1, shh, ptc). RESULTS: Depending on three major morphologic phenotypes of tumor cell xenotransplants (ductal (YAPC), ductal/solid (DAN-G, CAPAN-1), solid (PANC-1, MIA PaCa-2)), a decrease of CK7/CK19 was found, accompanied by an increase of CK8/18 and vimentin. Predominantly the CK7-positive ductal phenotype (YAPC and DAN-G) was associated with pdx-1 expression, whereas the CK8-positive solid phenotype was associated with shh/ptc expression on protein and mRNA level. Additionally, CK-20 expression was mainly linked to the ductal phenotype, co-localized with nuclear beta-catenin. The endocrine-exocrine transdifferentiation, as assessed by Chr-A and alpha1-chym, was on a constant low to moderate level in all xenotransplants. Finally, an intensive epithelial-mesenchymal interaction was observed by overexpression of laminin-5 at the invasion front. CONCLUSION: The observed patterns of morphology and molecular differentiation in human pancreatic cancer xenografts indicate that these cancer cell lines have different capabilities of pattern formation in vivo associated with molecular differentiation markers, especially of embryonic pancreatic development.

Adenocarcinoma↗
PubMed2005

The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells.

Treatment for advanced stages of hepatocellular carcinoma (HCC) remains unsatisfactory. While 5-fluorouracil (5-FU) and irinotecan are first-line treatment options for other gastrointestinal tumors, their effect on HCCs is low. Histone-deacetylase inhibitors such as suberoylanilide hydroxamic acid (SAHA) have shown antitumoral activity at micromolar concentrations in a variety of human cancers in vitro and in vivo. Here, we investigated the effects of a combination of 5-FU, irinotecan and SAHA on growth inhibition and apoptosis induction in HCC cell lines. HepG2, Hep1B and MH-7777A hepatoma cell lines and human foreskin fibroblasts as non-transformed controls were incubated with 5-FU, irinotecan and SAHA either alone or in combination. While the single agents did not show any effects on growth of the cell lines, the combination of 5-FU and irinotecan (both 10 microM) led to a moderate increase in apoptosis and proliferation inhibition. Adding 1 microM SAHA increased the apoptosis rate in hepatoma cell lines up to 92% after 72 h, while fibroblasts showed no response (5.5% apoptosis). Induction of apoptosis was paralleled by loss of the mitochondrial transmembrane potential, downregulation of bcl-2 expression and activation of caspase 3 but not caspase 8. In summary, SAHA sensitized HCC cell lines for treatment with an otherwise ineffective combination of 5-FU and irinotecan and led to mitochondrial apoptosis induction. The use of the triple combination could optimize treatment results in vivo and needs further evaluation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Potentiated anticancer effects on hepatoma cells by the retinoid adapalene.

Retinoids can block cell proliferation and induce apoptosis in tumor cells. The antitumoral effect of synthetic retinoids like Adapalene (ADA) on hepatoma cells (HepG2, Hep1B) was investigated. Cell proliferation was assessed by measuring DNA synthesis and apoptosis by flow cytometry and immunocytochemistry. Cell cycle- and apoptosis-associated proteins were semi-quantified by Western Blotting and breakdown of mitochondrial membrane potentials was detected by JC-1 staining. ADA at 10(-4)M efficiently induced apoptosis, reaching 61.7% in HepG2 and 79.1% in Hep1B after 72 h incubation. This was accompanied by up-regulation of pro-apoptotic bax and caspase 3, while bcl-2 was down-regulated, shifting the bax/bcl-2 ratio to >2.3 in hepatoma cells. ADA inhibits hepatoma cell growth in vitro and is a powerful inducer of hepatoma cell apoptosis.

Adapalene↗
PubMed2004

The combination of tamoxifen and 9cis retinoic acid exerts overadditive anti-tumoral efficacy in rat hepatocellular carcinoma.

BACKGROUND/AIMS: Medical treatment for hepatocellular carcinoma (HCC) remains elusive. While an acyclic retinoid improved tumor-free survival after hepatoma resection, tamoxifen finally proved ineffective. Combination therapy of both agents has not been investigated in vitro and in vivo. METHODS: MH7777A hepatoma cells were incubated with tamoxifen (TAM) and 9-cis retinoic acid (CRA) alone or in combination. Proliferation rate and apoptosis were assessed by BrdU incorporation and flow cytometry. In vivo efficacy was studied using the Morris hepatoma model in immunocompetent rats. End points were macroscopic tumor growth, metastasis and immunohistochemistry for proliferative and apoptotic tumor cells (PCNA and TUNEL staining). RESULTS: In vitro, CRA and TAM monotherapy was effective only in the highest concentration. Combination therapy significantly enhanced apoptosis rate and growth inhibition in hepatoma cells. While in vivo monotherapy did not reduce tumor growth or metastasis, their combination reduced tumor size after 28 days by 64.5+/-28%. This was paralleled by an increase in TUNEL positive and a decrease in PCNA positive cells. CONCLUSIONS: The combination of TAM and CRA enhances their anti-tumoral efficacy in vitro as well as in vivo, while monotherapy is ineffective. This combination could be a promising adjunctive therapy of HCC.

Alitretinoin↗
PubMed2004

A quadruple therapy synergistically blocks proliferation and promotes apoptosis of hepatoma cells.

Effective therapy for advanced hepatocellular carcinoma (HCC) is lacking. Conventional chemotherapy was judged to be ineffective. We previously demonstrated that the histone deacetylase inhibitor Trichostatin A (TSA) blocks growth of HCC cells in vitro. The anti-tumoral effect of a combination of more than 2 classes of drugs remains unexplored. Four hepatoma cell lines were incubated with increasing concentrations of Tamoxifen (TAM), 9-cis retinoic acid (CRA), the methioninaminopeptidase inhibitor TNP-470 and TSA as single agents and in combination. Anti-proliferative and pro-apoptotic effects were assessed using BrdU-incorporation, FACS analysis and immunocytochemistry. Central pro- and anti-apoptotic proteins were measured by semi-quantitative Western blotting and substrate assays. All single substances inhibited proliferation and induced apoptosis in HCC cells only at high concentrations. The combination of TAM/CRA/TNP/TSA multiplied the anti-tumoral effects, reaching up to 93% inhibition of proliferation and 63% induction of apoptosis after 24 h in Hep1B cells. Pro-apoptotic factors bax and caspase 3 were highly increased with quadruple therapy, while anti-apoptotic bcl-2 decreased to undetectable levels. Fibroblasts remained largely unaffected. While the single substances were not effective on hepatoma cells in tolerable doses, their combination significantly increases anti-tumoral efficacy. Combination therapy with biomodulators is a promising treatment option for HCC.

Animals↗
PubMed2003

The synthetic retinoid adapalene inhibits proliferation and induces apoptosis in colorectal cancer cells in vitro.

Chemotherapy of advanced stages of colorectal carcinoma is unsatisfactory. Retinoids inhibit cell growth and induce apoptosis in a variety of human malignancies. We compared the effect of the synthetic retinoid adapalene (ADA) and 9-cis-retinoic acid (CRA) on carcinoma cell lines in vitro. Colon carcinoma cell lines CC-531, HT-29 and LOVO as well as human foreskin fibroblasts were exposed to different concentrations of ADA and CRA for 3-72 hr. Proliferation was assessed by BrdU incorporation and apoptosis by FACS analysis. Breakdown of DeltaPsi(m) was determined by JC-1 staining and activity of caspases 3 and 8, by a colorimetric assay. Quantitative Western blots were performed to detect changes in bax, bcl-2 and caspase-3. Both retinoic derivatives suppressed DNA synthesis and induced apoptosis in all tested cell lines time- and dose-dependently. While the natural retinoid CRA showed moderate antiproliferative and proapoptotic effects only at the highest concentration (10(-4) M), the synthetic retinoic ADA was significantly more effective, showing remarkable effects even at 10(-5) M. ADA and CRA disrupt DeltaPsi(m) and induce caspase-3 activity in responsive tumor cells. Quantitative Western blots showed a shift of the bax:bcl-2 ratio toward proapoptotic bax in ADA-treated cells. Our results clearly indicate the superiority of ADA compared to CRA. Therefore, we suggest that ADA may be far more suitable as an adjunctive therapeutic agent for treatment of colon cancer in vivo.

Adapalene↗
PubMed2003

Overadditive anti-proliferative and pro-apoptotic effects of a combination therapy on colorectal carcinoma cells.

The prognosis of advanced colorectal carcinoma (CC) is poor. Established chemotherapy shows only limited efficacy but significant side effects. We investigated how far a combination of tamoxifen (TAM), 9-cis-retinoic acid (CRA) and the fluoroquinolone ciprofloxacin (CIP) synergize to inhibit proliferation and promote apoptosis of CC cells in vitro. The CC cell lines LOVO, CC-531 and SW-403 were incubated with TAM, CRA and CIP (10(minus;4)-10(minus;6) M) as single agents and in combination. Cell proliferation was assessed by bromodeoxyuridin incorporation. Apoptosis was quantified immunohistochemically and by FACS analysis after staining with propidium iodide. Changes in the expression of caspase 3, bax, bcl-2 and p21cip/waf were assessed by quantitative Western blotting. CRA and TAM monotherapy was moderately effective. Their combination enhanced apoptosis from 60% to more than 80% in all cell types. Apoptosis was paralleled by inhibition of proliferation and further potentiated by addition of CIP. The combination effectively up-regulated caspase 3 and bax and down-regulated bcl-2 and p21cip/waf. Combinations of biomodulaters act synergistically to inhibit proliferation and promote apoptosis in CC cells. Due to their known safety profile, this justifies clinical trials for colorectal cancer using combinations of these biological response modifiers.

Alitretinoin↗
PubMed2002

The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells.

BACKGROUND/AIMS: Effective treatment for hepatocellular carcinoma is urgently needed. The histone-deacetylase inhibitor Trichostatin A (TSA) was shown to induce apoptosis in non-hepatic cells at submicromolar concentrations. However, the effect of TSA on hepatoma cells is unknown. METHODS: The hepatoma cells HepG2, MH1C1, Hepa1-6 and Hep1B as well as human fibroblasts (control cells) were exposed to TSA (10(-6) to 10(-9)M). Cell proliferation was assessed by measuring DNA-synthesis and cell numbers. Apoptosis was quantified by flow cytometry and by the TdT-mediated dUTP nick-end labeling method. Expression patterns of cell cycle- and/or apoptosis-associated p27, p21(cip/waf), bax, bcl-2, cyclin A and (pro)-caspase 3 were studied using quantitative Western blotting. Activation of caspase 3 was analyzed via a colorimetric assay. RESULTS: 10(-6)M TSA inhibited DNA-synthesis by 46% (HepG2) to 64% (MH1C1) after 24h, inducing a G(2)/M-phase arrest and apoptosis. TSA increased activation of caspase 3 and expression of cyclin A, p2l(cip/waf), bax and (pro)-caspase 3, while bcl-2 was downregulated. Human fibroblasts remained unaffected. CONCLUSIONS: TSA inhibits hepatoma cell growth in vitro, which are otherwise particularly resistant to chemotherapy. Its anti-proliferative activity is paralleled by a comparable rate of apoptosis. TSA may be a promising agent for treatment of hepatocellular carcinoma in vivo.

Apoptosis↗
PubMed2002

Can quantitative tests of liver function discriminate between different etiologies of liver cirrhosis?

Studies comparing quantitative testing of liver function (QTLF) in large numbers of patients with defined etiology of cirrhosis are lacking. In all 316 patients with proven cirrhosis underwent QTLF, including aminopyrine breath test (ABT), galactose elimination capacity (GEC), sorbitol (SCI), and indocyanine green clearance (ICG). Values were correlated with the Child-Pugh classification (CP) and the etiology of liver cirrhosis. Fifty-five percent of the patients had alcoholic cirrhosis (ALC), 31% cirrhosis due to viral hepatitis (VIC), and 14% primary biliary cirrhosis (PBC). In all three groups there was a decrease of QTLF levels from CP grade A to C, which differed from normal values. QTLF was most compromised in patients with ALC and VIC compared to patients with PBC. In conclusion, QTLF in ALC and VIC patients was more reduced than in patients with PBC. This may be due to saturation of enzymes in ALC and ongoing inflammation in VIC.

Aged↗
PubMed2002

Quantitative testing of liver function compared to prognostic scores in patients with primary biliary cirrhosis.

AIM: Primary biliary cirrhosis (PBC) is a slowly progressive liver disease which can lead to cirrhosis. We investigated if quantitative tests of liver function (QTLF) and serum levels of a surrogate marker of hepatic fibrogenesis (PIIINP) provide information in addition to established prognostic scores. METHODS: In 34 PBC patients PIIINP, PBC-relevant parameters, histological staging and QTLF at entry and at 2 years were determined and compared with the Christensen (CPS I, CPS II) and Mayo prognosis score. QTLF included aminopyrine breath test, galactose elimination capacity, sorbitol and indocyanine green clearance. RESULTS: Bilirubin, serum IgM and PIIINP were elevated at both time points, whereas albumin and prothrombin time remained normal. Clinical findings (ascites, cirrhosis, central cholestasis) and histological staging worsened after 2 years, as did the CPS II. However, QTLF, PIIINP, CPS I and the Mayo score revealed no significant changes. CONCLUSIONS: Only CPS II changed after 2 years, whereas CPS I and the Mayo score remained unaltered. QTLF and PIIINP did not provide any further information on progression of PBC, suggesting that QTLF cannot predict prognosis of PBC patients in a two-year interval and that CPS II is superior to CPS I and the Mayo score in short-term studies for PBC.

Aminopyrine↗
PubMed2002

Prognosis of a large cohort of patients with hepatocellular carcinoma in a single European centre.

BACKGROUND/AIM: Only a few follow up data are available for patients with hepatocellular carcinoma (HCC) in Europe and the USA. Therefore, we analysed all HCC patients admitted to our hospital between 1988 and 1999. METHODS: We documented aetiology, stage (HCC: Okuda and UICC classifications, liver cirrhosis: Child-Pugh score), and diagnostic and therapeutic measures of 281 consecutive HCC patients. Survival time was calculated as a function of staging and therapy. RESULTS: Cirrhosis was diagnosed in all patients. Seventy-two patients underwent liver resection, 28 liver transplantation, 31 transarterial chemoembolization and 14 percutaneous ethanol injection. One hundred and thirty-six patients received no treatment. The Okuda and the Child-Pugh classification predicted a significant decrease of median survival time, whereas the UICC classification was less powerful. CONCLUSIONS: HCC occurred only in patients with liver cirrhosis. Survival time correlated with therapy (or no therapy) and with the Child-Pugh Score. In European patients the Okuda classification is superior to the UICC classification and should be compared to novel classification systems.

Carcinoma, Hepatocellular↗
PubMed1992

RETRACTED: Right ventricular function in patients with reduced left ventricular function undergoing myocardial revascularization.

Complex interrelationships exist between the right (RV) and the left ventricles (LV). Therefore, in 30 consecutive patients with reduced LV function (left ventricular ejection fraction [LVEF]) less than 40% undergoing myocardial revascularization, RV hemodynamics were studied from the beginning of anesthesia until the end of the operation. The data were compared with 30 consecutive patients with normal LVEF (greater than 70%). Ventricular function was assessed during left heart catheterization, which was carried out within 1 month of the operation. In addition to standard hemodynamic variables, RV ejection fraction (RVEF), RV end-diastolic volume (RVEDV), and RV end-systolic volume (RVESV) were monitored by the thermodilution technique. The two groups did not differ preoperatively with regard to RVEF, pressure (MAP, PAP, PCWP, RAP, RVPsyst, RVEDP), cardiac index (CI), and volume variables (RVESV, RVEDV). However, when the group with preoperatively reduced LVEF was subdivided into patients with severely reduced LVEF (less than 30%; n = 14; mean value 25.1%) and patients with moderately reduced LVEF (30%-40%; n = 16; mean value 37.3%), RVEF was significantly lower in the patients with a LVEF below 30% throughout the entire investigation period. RVEDV and RVESV were significantly higher in these patients. In conjunction with the lower RVEF and normal PAP, this suggests reduced RV function. It can be concluded that a severely reduced preoperative LVEF (less than 30%) may also be associated with impaired RV function.

Analysis of Variance↗
PubMed1991

RETRACTED: Acute preoperative hemodilution in cardiac surgery: volume replacement with a hypertonic saline-hydroxyethyl starch solution.

Preoperative hemodilution (HD) is a recommended practice in cardiac surgery that conserves blood and reduces the complications of homologous blood transfusion. In 45 patients undergoing myocardial revascularization, HD was performed preoperatively. Withdrawn volume (10 mL/kg) was replaced either by a new hypertonic saline (HS) solution prepared in hydroxyethyl starch (HES) (2,400 mOsm/L, HS-HES group, n = 15) or by a standard low molecular weight hydroxyethyl starch solution (6% HES 200/0.5, HES group, n = 15) to maintain baseline PCWP (acute normovolemic hemodilution [ANH]). Fifteen comparable patients without HD served as controls. Significantly less HS-HES (210 +/- 20 mL) than HES 6% (890 +/- 90 mL) was necessary to sustain hemodynamics during HD. Stable cardiocirculatory conditions were obtained even after termination of bypass. Fluid balance during cardiopulmonary bypass as well as in the postoperative period was significantly lower in HS-HES-treated patients. With regard to hemodynamics, CI increased most in the HS-HES group (+36%), whereas systemic vascular resistance was lower in these patients. Right ventricular ejection fraction increased only in HS-HES patients (+15%). However, sodium concentration as well as osmolarity increased after volume replacement with HS-HES, without exceeding normal values. None of the patients suffered from organ failure. Pulmonary gas exchange (PaO2) was less compromised in the HS-HES patients. There were no renal function differences between the groups. In conclusion, HS solution prepared in HES is an attractive alternative for blood substitution in cardiac patients undergoing acute hemodilution for blood conservation.

Atrial Function, Right↗
PubMedDate not supplied

Changes in hepatic perfusion after administration of hydroxyethyl starch in intensive care patients assessed using color-coded Doppler sonography.

Using color-coded Doppler sonography (CCDS), changes in the resistance index of the hepatic artery (HA-RI) and in the velocities of the hepatic artery, portal and splenic vein (HA-V, PV-V, SV-V) were measured after administration of hydroxyethyl starch (HES) in 50 intensive care patients. PV-V and SV-V increased, whereas HA-V and HA-RI remained unchanged. CCDS is suitable to assess liver perfusion in intensive care patients. Since HES enhances splanchnic perfusion, its application improves hepatic perfusion in intensive care patients.

Blood Flow Velocity↗