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Lawrence E Harrison

Publications and source records attributed to Lawrence E Harrison.

14 recordsLinked to original sources
PubMed2006

CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation.

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family and has been studied mainly in the differentiation of post-mitotic neurons. The purpose of this study was to determine the presence of cdk5 expression and activity in colon cancer cells and to investigate its role in the regulation of PPARgamma ligand-induced antiproliferation. We observed that cdk5 protein levels and kinase activity were elevated in both HT-29 cells and human tumor tissue in comparison to decreased levels in normal colonic mucosa. To elucidate cdk5's role in PPARgamma ligand-induced antiproliferation of colon cancer cells, HT-29 cells were treated with ciglitazone. A dose- and time-dependent decrease in cell proliferation were observed after ciglitazone exposure, which correlated with a decrease in cdk5 protein expression and kinase activity. Importantly, these ciglitazone-induced antiproliferative changes were reversed when cdk5 was overexpressed. Although present, p35, the regulatory protein of cdk5, showed no significant changes in protein expression with the introduction of ciglitazone. This is the first report of cdk5/p35 expression and kinase activity in colon cancer cells, which is associated with ciglitazone-induced antiproliferation in HT-29 cells.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Cytoreductive surgery and intraoperative hyperthermic chemoperfusion for advanced ovarian carcinoma.

BACKGROUND: Optimal cytoreductive surgery combined with intraoperative hyperthermic chemoperfusion (IHCP) is a therapy that potentially could improve survival in a select group of patients with advanced ovarian cancer. The purpose of this study was to review the results of cytoreductive surgery and IHCP for advanced ovarian cancer and to identify factors that may predict which patients maximally benefit from this aggressive treatment. METHODS: Patients treated with cytoreduction followed by IHCP for ovarian cancer were identified from an IHCP database from 1/2001 through 3/2004. Several factors including resection status, peritoneal cancer index (PCI), and prior surgery were evaluated for their ability to predict survival in our cohort of patients. RESULTS: Thirteen patients with ovarian cancer treated with cytoreductive surgery followed by IHCP were identified. The 3-year overall survival rate for all thirteen patients was 55%. The median disease-free survival was 15.4 months (3-year disease-free survival, 11%). Several factors including PCI score (<6), ability to resect all gross disease, and previous surgical exploration appeared to impart an overall survival advantage. CONCLUSIONS: The use of IHCP coupled with optimal cytoreduction is a safe and effective treatment for advanced ovarian carcinoma. However, the proper selection of patients who will benefit most from the therapy is essential for the success of the treatment.

Adult↗
PubMed2005

Ciglitazone induces early cellular proliferation and NF-kappaB transcriptional activity in colon cancer cells through p65 phosphorylation.

While it is well established that peroxisome proliferator activated receptor gamma (PPARgamma) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARgamma exposure are less clear. In this report, we demonstrate that the PPARgamma ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-kappaB transcriptional activity. Ciglitazone exposure did not affect NF-kappaB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-kappaB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARgamma ligand exposure is associated with activation of NF-kappaB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.

Blotting, Western↗
PubMed2005

Ciglitazone-induced p27 gene transcriptional activity is mediated through Sp1 and is negatively regulated by the MAPK signaling pathway.

We have previously demonstrated that the PPARgamma ligand, ciglitazone, increases p27kip1 protein levels in HT-29 colon cancer cells through both inhibition of proteasome associated degradation and activation of transcriptional activity. [F. Chen, L.E. Harrison, Cell Signal. 17 (2005) 809] The purpose of this investigation was to further elucidate the mechanism of ciglitazone-induced activation of p27 gene transcription. We observed that the region -774/-462 of the p27 promoter plays a key role in ciglitazone-induced gene transcriptional activity and this region contains two Sp1 binding sites. When the p27PF-luc reporter was co-transfected with Sp1 expression plasmids, ciglitazone-induced p27PF-luc activity significantly increased, while mithramycin A, a Sp1 inhibitor, was able to abrogate its effects. Ciglitazone exposure increased both Sp1 protein expression and Sp1-DNA binding, which was also associated with a decrease of Erk1/2 phosphorylation. A similar increase of Sp1-DNA binding was observed when phosphorylation of Erk1/2 was inhibited by pretreatment with the MAP kinase inhibitor, U0126. In addition, a significant increase of p27PF-luc reporter luciferase activity was noted after MAP kinase inhibition, which could be abolished with co-treatment with mithramycin A. Based on these data, we postulate that ciglitazone induces p27 gene transcription through increased Sp1 binding to its promoter region, which in turn is mediated through increased Sp1 protein levels and decreased inhibitory regulation by the MAP kinase pathway.

Binding Sites↗
PubMed2005

Partial hepatectomy for metastases from noncolorectal, nonneuroendocrine carcinoma.

OBJECTIVE: To define perioperative and long-term outcome and prognostic factors in patients undergoing hepatectomy for liver metastases arising from noncolorectal and nonneuroendocrine (NCNN) carcinoma. SUMMARY BACKGROUND DATA: Hepatic resection is a well-established therapy for patients with liver metastases from colorectal or neuroendocrine carcinoma. However, for patients with liver metastases from other carcinomas, the value of resection is incompletely defined and still debated. METHODS: Between April 1981 and April 2002, 141 patients underwent hepatic resection for liver metastases from NCNN carcinoma. Patient demographics, tumor characteristics, treatment, and postoperative outcome were analyzed. RESULTS: Thirty-day postoperative mortality was 0% and 46 of 141 (33%) patients developed postoperative complications. The median follow up was 26 months (interquartile range [IQR]) 10-49 months); the median follow up for survivors was 35 months (IQR 11-68 months). There have been 24 actual 5-year survivors so far. The actuarial 3-year relapse-free survival rate was 30% (95% confidence interval [CI], 21-39%) with a median of 17 months. The actuarial 3-year cancer-specific survival rate was 57% (95% CI, 48-67%) with a median of 42 months. Primary tumor type and length of disease-free interval from the primary tumor were significant independent prognostic factors for relapse-free and cancer-specific survival. Margin status was significant for cancer-specific survival and showed a strong trend for relapse-free survival. CONCLUSIONS: Hepatic resection for metastases from NCNN carcinoma is safe and can offer long-term survival in selected patients. Hepatic resection should be considered if all gross disease can be removed, especially in patients with metastases from reproductive tract tumors or a disease-free interval greater than 2 years.

Adrenal Cortex Neoplasms↗
PubMed2004

Ciglitazone-induced cellular anti-proliferation increases p27kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation.

While it is well established that PPARgamma ligands inhibit cell growth and induce apoptosis in colon cancer cells, the mechanism of these effects of PPARgamma ligands is unclear. In this report, we demonstrate that the PPARgamma ligand, ciglitazone, exhibits an anti-proliferative effect and blocks G1/S cell cycle progression through regulation of p27kip1 protein levels and inhibition of Cdk2 activity in HT-29 colon cancer cells. The ciglitazone-induced G1/S cell cycle arrest was noted only after 72 h of exposure, corresponding to elevated protein levels of p27kip1. However, an increase in p27kip1 protein synthesis as evidenced by increased p27kip1 gene promoter activity and mRNA abundance was observed as early as 24 h after exposure to ciglitazone. Proteasome activity, an additional mechanism of p27kip1 regulation, was dramatically inhibited after ciglitazone exposure, but only after 72 h of exposure. We also note that the effects of ciglitazone on p27kip1 gene regulation are PPRE independent. These data suggest that ciglitazone-induced G1/S arrest is through Cdk2 inhibition and an increase of p27kip1 protein levels which in turn is due a balance of ciglitazone's affect on new protein synthesis and degradation.

CDC2-CDC28 Kinases↗
PubMed2004

Racial discrepancies in the outcome of patients with hepatocellular carcinoma.

HYPOTHESIS: There is a marked variation in the outcome of patients with hepatocellular carcinoma with respect to race and ethnicity. Rates among African American and Hispanic individuals are elevated as compared with those among white individuals. DESIGN: Retrospective review of a prospective database. Demographic information, clinical staging, and other defining factors, including the absence or presence of hepatitis, cirrhosis, and alcohol abuse, were analyzed by patient interviews and review of the medical record. SETTING: Urban tertiary referral teaching hospital. PATIENTS: Patients diagnosed as having hepatocellular carcinoma between July 1997 and June 2003 (N = 264). Main Outcome Measure Overall survival rates. RESULTS: Based on multivariate analysis, race was identified as an independent predictor of survival. While there was no difference in the distribution of patient or tumor characteristics between the 2 groups, African American/Hispanic patients had a 5-year survival rate of 12%, which was significantly lower than that of white patients (50%; P = .001). CONCLUSIONS: This study demonstrates a significant discrepancy in overall survival of African American/Hispanic patients as compared with that of white patients. The reason for this difference cannot be explained by patient or tumor characteristics or completely by treatment allocation. These data suggest that there may be socioeconomic, biological, and/or cultural determinants contributing to this observed difference in outcome.

Adult↗
PubMed2003

Phosphorylation of PPARgamma via active ERK1/2 leads to its physical association with p65 and inhibition of NF-kappabeta.

Peroxisome proliferator-activated receptors (PPAR) are novel nuclear receptors and PPARgamma ligands have been shown to produce pro-apoptotic effects in many cancer cell types, including colon cancer. PPARgamma ligands exert their effect through PPARgamma-dependent (genomic) and PPARgamma-independent (non-genomic) mechanisms. Recent evidence suggests that PPARgamma ligands exert their pro-apoptotic effects in part by directly antagonizing the NF-kappabeta pathway as well as through activation of the MAP kinase pathway. In this report, we have demonstrated that ciglitazone, a member of the thiazoldinedione class of PPARgamma ligands induces HT-29 colon cancer cells to undergo apoptosis and prior to apoptosis, ciglitazone exposure results in a transient phosphorylation of PPARgamma. This phosphorylation of PPARgamma was mediated through the ciglitazone-induced activation of Erk1/2. PPARgamma phosphorylation affected the genomic pathway by being inhibitory to PPARgamma-DNA binding and PPRE transcriptional activity, as well as the non-genomic pathway by increasing the physical interaction of PPARgamma with p65, leading to the inhibition of NF-kappabeta. Ciglitazone induced phosphorylation of PPARgamma through the MAP kinase pathway provides a potential regulatory mechanism for PPARgamma's physical interaction with p65, leading to inhibition of NF-kappabeta and subsequent apoptosis.

Apoptosis↗
PubMed2003

Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Enthusiasm for radiofrequency ablation (RFA) therapy for patients with unresectable hepatocellular carcinoma (HCC) has increased. The data for recurrence after RFA for patients with HCC is not well documented. The purpose of this study was to evaluate tumor recurrence patterns after RFA in patients with unresectable HCC. STUDY DESIGN: Over a 3-year period, 50 patients having RFA for unresectable HCC were identified at a single institution. Medical records and radiologic studies were reviewed and outcomes factors analyzed. RESULTS: Of the entire cohort, 46 patients underwent RFA by a percutaneous approach under CT guidance. Most patients underwent either one (n = 22) or two ablations (n = 23). At the time of this report, 14 patients (28%) were tumor-free by radiologic and biochemical (alpha-fetoprotein) parameters. Eighteen additional patients had persistence of tumor at the ablation site and 14 patients had recurrence in the liver at sites different from the ablation site. An additional four patients had recurrence in extrahepatic sites. Twelve patients underwent orthotopic liver transplantation after RFA. Of these 12, 5 (42%) demonstrated no viable tumor in the explanted liver. Independent predictors of tumor recurrence included tumor size, serum AFP levels, and the presence of hepatitis. CONCLUSIONS: These data suggest that factors such as tumor size should be considered before employing RFA therapy. In addition to treating the primary tumor, other therapies aimed at the liver's inflammatory state might also be important in achieving a durable response after RFA.

Adult↗
PubMed2002

Exposure to a deuterated analogue of phenylbutyrate retards S-phase progression in HT-29 colon cancer cells.

Differentiation agents that induce neoplastic cells to regain a normal phenotype and/or cause growth arrest without significantly affecting normal cells represent an attractive option for cancer treatment. Analogues of short chain fatty acids, such as phenylbutyrate (PB), have been studied as clinically relevant agents. In an attempt to improve its pharmacokinetic profile, structural modifications of PB and other fatty acids have been studied. We hypothesize that strategic isotopic modification of PB would result in a longer half-life and thus translate into a more potent differentiation agent for clinical use. Using a colon cancer model, we demonstrated that 2,2,3,3-tetradeuterated PB (D4PB) significantly increased induction of apoptosis and inhibition of cell proliferation as compared with PB and butyrate. Difference in potency could not be explained by the effect of D4PB on the expression of specific regulatory proteins of the apoptotic cascade or from the inhibitory effect of D4PB on histone deacetylase activity. Interestingly, exposure of HT-29 colon cancer cells to D4PB resulted in a slowing of S transit, in contrast to butyrate and PB, which induced a G2/M cell cycle block. This difference in cell cycle effect may explain the differences seen in the potency of the phenotypic changes seen with treatment with D4PB. Further studies are needed to elucidate the mechanisms underlying effects of D4PB on the cell cycle.

Apoptosis↗
PubMed2002

Phenylbutyrate-induced apoptosis is associated with inactivation of NF-kappaB IN HT-29 colon cancer cells.

PURPOSE: Cytotoxic chemotherapy has been used to treat patients with metastatic colorectal cancer with limited success. Therefore novel chemotherapeutic approaches are needed. Based on encouraging preclinical data, there has been an interest in developing derivatives of butyrate as clinically applicable agents. The purpose of this study was to investigate the effects of phenylbutyrate (PB), a butyrate analogue, on the cell growth and apoptosis in a colon cancer cell model. METHODS: Growth curves, flow cytometric studies, Western blotting, DNA binding assays and transient transfection experiments were performed in vitro using the colon cancer cell line HT-29 after exposure to PB. RESULTS: Exposure of HT-29 colon cancer cells to PB resulted in growth inhibition and induction of apoptosis as measured by annexin V staining. This increase in apoptosis was associated with a decrease in mitochondrial membrane potential, an increase in caspase-3 activity and a decrease in intact PARP protein levels. Since NF-kappaB plays a pivotal role in the regulation of apoptosis, we explored the effects of PB on the DNA binding and transcriptional activity of this transcription factor. After PB treatment, NF-kappaB-DNA binding was markedly decreased and specifically, this decreased DNA binding was observed in the p50:p65 heterodimer. The decreased NF-kappaB DNA binding was observed as early as 3 h after PB treatment, while no apparent changes in annexin V binding were detected until 12 h after PB treatment. Untreated HT-29 cells transfected with a kappaB-luciferase reporter plasmid demonstrated significant constitutive activity of the kappaB binding site, which was markedly decreased after treating the cells with PB. CONCLUSION: These results suggest that PB-induced apoptosis may be partly regulated through the inactivation of NF-kappaB. PB, an oral butyrate analogue, may have therapeutic potential in colon cancer.

Annexin A5↗
PubMedDate not supplied

Hepatitis status, child-pugh classification, and serum AFP levels predict survival in patients treated with transarterial embolization for unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents one of the most prevalent cancers worldwide. Most patients are not surgical candidates, and transarterial embolization (TAE) has been used to treat patients with unresectable HCC. The purpose of this study was to identify factors that predict survival in patients treated with TAE at a Western medical center. Review of a prospective database identified 345 patients treated for HCC at University Hospital (Newark, NJ) between July 1998 and July 2004. Of these patients, 109 patients underwent TAE. Eleven of these patients were subsequently treated surgically and excluded from this study. Of the remaining 98 patients, demographic data and laboratory values were analyzed to predict survival by univariate and multivariate analysis. Several factors, including hepatitis status, Child-Pugh classification, serum alpha fetoprotein levels <500 ng/ml, bilirubin <2.0 mg/dl, prothrombin time <16 seconds, platelet count <200 x 10(9)/l, albumin >3.5 gm/dl, and multiple treatments, predicted survival by univariate analysis. Serum alpha fetoprotein levels, Child-Pugh classification, and hepatitis status were found by multivariate analysis to independently predict survival. These factors may help to select patients with unresectable HCC who might benefit from TAE.

Adult↗