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Biomedical subjects

D Coppola

Publications and source records attributed to D Coppola.

At least 19 recordsLinked to original sources
PubMed2002

RDP58, a locally active TNF inhibitor, is effective in the dextran sulphate mouse model of chronic colitis.

OBJECTIVE AND DESIGN: RDP58 is a novel anti-inflammatory peptide that inhibits TNF synthesis and upregulates heme oxygenase-1. RDP58 therapy was evaluated in the dextran sodium sulphate (DSS) model of chronic colitis. MATERIAL: Colitis was induced by giving DSS to mice (n = 8 animals/group). Toxicity studies were done in Rhesus monkeys (n = 5), dogs (n = 3) and mice (n = 10). TREATMENT: In colitis, mice were treated with p.o. vehicle (saline), RDP58 (5 and 10 mg/kg/day) or 5-ASA (50 mg/kg/day). METHODS: Disease activity index (DAI) was used as the endpoint of efficacy. RESULTS: RDP58 therapy significantly reduced DAI and histological scores in all animals. DAI scores in RDP58 treated animals declined faster than 5-ASA. RDP58 at 5 or 10 mg/ kg/day significantly reduced DAI compared to 5-ASA. RDP58 significantly reduced acute, chronic and total inflammation scores. It enhanced re-epithelialization by reducing crypt scores. RDP58 was not bioavailable and was well tolerated. CONCLUSIONS: Therapeutic efficacy of RDP58 combined with a lack of bioavailibility and toxicity suggest that RDP58 may be a promising new therapeutic for IBD.

Animals↗
PubMed2002

Electrically mediated delivery of vector plasmid DNA elicits an antitumor effect.

In vivo electroporation is an efficient means of increasing plasmid DNA delivery to normal tissues, such as skin and muscle, as well as directly to tumors. In the experiments described here, plasmid DNA was delivered by in vivo electroporation to B16 mouse melanomas using two very different pulsing protocols. Reporter expression increased 21- or 42-fold, respectively with electroporation over injection alone. The growth of experimental melanomas with an approximate diameter of 4 mm on the day of treatment was monitored after electroporation delivery of reporter plasmid DNA. Remarkably, short-term complete regressions using one of these pulsing protocols occurred in up to 100% of mice. These regressions continued long term in up to 83% of animals. 70% of these mice were resistant to challenge with B16 melanoma cells. Histological analysis revealed large numbers of apoptotic cells 24 h after treatment. This antitumor effect did not require therapeutic cDNA expression or eukaryotic sequences.

Animals↗
PubMed2001

Loss of MHC class II inducibility in hyperplastic tissue in Rb-defective mice.

Retinoblastoma gene (Rb) defects occur frequently in human tumors. Studies of Rb-defective human tumor cell lines and Rb-/- murine embryonic fibroblasts demonstrate that Rb is required for interferon-gamma (IFN-gamma) induced major histocompatibility complex (MHC) class II expression. MHC class II expressing tumors generate anti-tumor immune responses associated with tumor-specific infiltrating lymphocytes. The role of Rb in IFN-gamma induced MHC class II expression on an endogenous tumor was examined by immunohistochemical staining for IAbeta and Rb on tissues from Rb+/- mice. MHC class II IAbeta is not induced by IFN-gamma in Rb-deficient neoplastic cells, but remains inducible in related normal tissue.

Animals↗
PubMed2001

Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K.

We have shown previously that the AKT2 pathway is essential for cell survival and important in malignant transformation. In this study, we demonstrate elevated kinase levels of AKT2 and phosphatidylinositol-3-OH kinase (PI3K) in 32 of 80 primary breast carcinomas. The majority of the cases with the activation are estrogen receptor alpha (ERalpha) positive, which prompted us to examine whether AKT2 regulates ERalpha activity. We found that constitutively activated AKT2 or AKT2 activated by epidermal growth factor or insulin-like growth factor-1 promotes the transcriptional activity of ERalpha. This effect occurred in the absence or presence of estrogen. Activated AKT2 phosphorylates ERalpha in vitro and in vivo, but it does not phosphorylate a mutant ERalpha in which ser-167 was replaced by Ala. The PI3K inhibitor, wortmannin, abolishes both the phosphorylation and transcriptional activity of ERalpha induced by AKT2. However, AKT2-induced ERalpha activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384, implicating that AKT2-activated ERalpha contributes to tamoxifen resistance. Moreover, we found that ERalpha binds to the p85alpha regulatory subunit of PI3K in the absence or presence of estradiol in epithelial cells and subsequently activates PI3K/AKT2, suggesting ERalpha regulation of PI3K/AKT2 through a nontranscriptional and ligand-independent mechanism. These data indicate that regulation between the ERalpha and PI3K/AKT2 pathway (ERalpha-PI3K/AKT2-ERalpha) may play an important role in pathogenesis of human breast cancer and could contribute to ligand-independent breast cancer cell growth.

Androstadienes↗
PubMed2001

CEP1612, a dipeptidyl proteasome inhibitor, induces p21WAF1 and p27KIP1 expression and apoptosis and inhibits the growth of the human lung adenocarcinoma A-549 in nude mice.

The ubiquitin proteasome system is responsible for the proteolysis of important cell cycle and apoptosis-regulatory proteins. In this paper we report that the dipeptidyl proteasome inhibitor, phthalimide-(CH2)8CH-(cyclopentyl) CO-Arg(NO2)-Leu-H (CEP1612), induces apoptosis and inhibits tumor growth of the human lung cancer cell line A-549 in an in vivo model. In cultured A-549 cells, CEP1612 treatment results in accumulation of two proteasome natural substrates, the cyclin-dependent kinase inhibitors p21WAF1 and p27KIP1, indicating its ability to inhibit proteasome activity in intact cells. Furthermore, CEP1612 induces apoptosis as evident by caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Treatment of A-549 tumor-bearing nude mice with CEP1612 (10 mg/kg/day, i.p. for 31 days) resulted in massive induction of apoptosis and significant (68%; P < 0.05) tumor growth inhibition, as shown by terminal deoxynucleotidyltransferase-mediated UTP end labeling. Furthermore, immunostaining of tumor specimens demonstrated in vivo accumulation of p21WAF1 and p27KIP1 after CEP1612 treatment. The results suggest that CEP1612 is a promising candidate for further development as an anticancer drug and demonstrate the feasibility of using proteasome inhibitors as novel antitumor agents.

Adenocarcinoma↗
PubMed2001

Effects of electrochemotherapy with bleomycin on normal liver tissue in a rat model.

Preliminary studies that used electric pulses in vivo to facilitate entry of chemotherapeutic agents into tumour cells resulted in a 69% complete response rate for hepatocellular carcinoma in rats. This success motivated a focused investigation to define the adverse effects of this treatment on normal liver tissue. Bleomycin doses ranging from 0.5 to 2.5 U and electric fields from 500 to 2250 V/cm were investigated. Electrical treatment was administered using an array of six needles arranged in a circular pattern. Necrosis and four other histological parameters were examined 14 and 56 days after treatment. Results indicated that treatment effects were localised to the volume of treated tissue. These parameters, at both time points, were not significantly altered for liver tissue that was treated with all drug doses and electric fields of 1250 V/cm and below. Only the combination of more intense electric pulses with bleomycin produced adverse histological events in the form of localised liver necrosis at day 14. These effects were not visible at day 56. Liver function was normal through all of the treatment except for an elevation of several enzymes 1 day post-treatment.

Animals↗
PubMed2001

Treatment of hepatocellular carcinoma in a rat model using electrochemotherapy.

The effectiveness of antineoplastic agents has been augmented by applying pulsed electric fields directly to tumours after the administration of the drug. This treatment, known as electrochemotherapy (ECT), has been successful for cutaneous malignancies in animal models and in recent clinical trials. This study was aimed at investigating the applicability of ECT in a surgical setting for hepatocellular carcinomas induced in the livers of rats. Established tumours were injected with bleomycin, and electric pulses were then administered locally. Animals were followed based on tumour volumes and histological samples. Dose response data were obtained for both electric field intensity and bleomycin. Complete response rates for animals treated with electrochemotherapy ranged from 26.67% to 93.33 and were durable. In contrast, tumours that received no treatment, pulses only or drug only responded minimally. This supports the feasibility of using a ECT as a modality for treating hepatocellular carcinoma.

Animals↗
PubMed2001

Antiproliferative and apoptotic effect of ascorbyl stearate in human glioblastoma multiforme cells: modulation of insulin-like growth factor-I receptor (IGF-IR) expression.

Human glioblastomas (gliomas) are characterized as highly invasive and rapidly growing brain tumors. In this study, we present data on in vitro effect of ascorbyl stearate (Asc-S), a liphophilic derivative of ascorbic acid on cell proliferation, transformation, apoptosis and modulation of expression of insulin-like growth factor-I receptor (IGF-IR) in human glioblastoma multiforme (T98G) cells. Asc-S showed significant inhibition of fetal bovine serum and human recombinant insulin-like growth factor-I (IGF-I) dependent cell proliferation in a dose dependent manner. Treatment of T98G cells with 0, 50, 100 and 150 microM Asc-S for 24h slowed down the cell multiplication cycle with significant accumulation of cells at late S/G2-M phase of cycle. Asc-S treatment (100 microM) reversed the transformed phenotype as determined by clonogenecity in soft agar and also induced apoptosis of T98G. These changes were found to be associated with significant decrease in IGF-IR expression in dose and time dependent manner compared to untreated controls. The data clearly demonstrate that Asc-S has antiproliferative and apoptotic effect on T98G cells probably through modulation of IGF-IR expression and consequent facilitation of programmed cell death.

Agar↗
PubMed2001

Local excision of T2 and T3 rectal cancers after downstaging chemoradiation.

OBJECTIVE: To evaluate the safety and efficacy of local excision in patients with T2 and T3 distal rectal cancers that have been downstaged by preoperative chemoradiation. SUMMARY BACKGROUND DATA: T2 and T3 cancers treated by local excision alone are associated with unacceptably high recurrence rates. The authors hypothesized that preoperative chemoradiation might downstage both T2 and T3 lesions and significantly expand the indications for local excision. METHODS: Local excision was performed after preoperative chemoradiation on patients with a complete clinical response or on patients who were either ineligible for or refused to undergo abdominoperineal resection. Local excision was approached transanally by removing full-thickness rectal wall and the underlying mesorectum. RESULTS: From 1994 to 2000, 95 patients with rectal cancers underwent preoperative chemoradiation and surgical resection for curative intent. Of these, 26 patients (28%), 19 men and 7 women, with a mean age of 63 years (range 44-90), underwent local excision. Pretreatment endoscopic ultrasound classifications included 5 T2N0, 13 T3N0, 7 T3N1, and 1 not done. Pathologic partial and complete responses were achieved in 9 of 26 (35%) and 17 of 26 (65%) patients, respectively. Two of nine partial responders underwent immediate abdominoperineal resection. The mean follow-up was 24 months (median 19, range 6-77). The only recurrence was in a patient who refused to undergo abdominoperineal resection after a partial response. There was one postoperative death from a stroke. This treatment was associated with a low rate of complications. CONCLUSION: Local excision appears to be an effective alternative treatment to radical surgical resection for a highly select subset of patients with T2 and T3 adenocarcinomas of the distal rectum who show a complete pathologic response to preoperative chemoradiation.

Adenocarcinoma↗
PubMed2000

Why are angles misperceived?

Although it has long been apparent that observers tend to overestimate the magnitude of acute angles and underestimate obtuse ones, there is no consensus about why such distortions are seen. Geometrical modeling combined with psychophysical testing of human subjects indicates that these misperceptions are the result of an empirical strategy that resolves the inherent ambiguity of angular stimuli by generating percepts of the past significance of the stimulus rather than the geometry of its retinal projection.

Female↗
PubMed2000

Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer.

We previously demonstrated that AKT2, a member of protein kinase B family, is activated by a number of growth factors via Ras and PI 3-kinase signaling pathways. Here, we report the frequent activation of AKT2 in human primary ovarian cancer and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase (PI 3-kinase)/Akt pathway. In vitro AKT2 kinase assay analyses in 91 ovarian cancer specimens revealed elevated levels of AKT2 activity (>3-fold) in 33 cases (36.3%). The majority of tumors displaying activated AKT2 were high grade and stages III and IV. Immunostaining and Western blot analyses using a phospho-ser-473 Akt antibody that detects the activated form of AKT2 (AKT2 phosphorylated at serine-474) confirmed the frequent activation of AKT2 in ovarian cancer specimens. Phosphorylated AKT2 in tumor specimens localized to the cell membrane and cytoplasm but not the nucleus. To address the mechanism of AKT2 activation, we measured in vitro PI 3-kinase activity in 43 ovarian cancer specimens, including the 33 cases displaying elevated AKT2 activation. High levels of PI 3-kinase activity were observed in 20 cases, 15 of which also exhibited AKT2 activation. The remaining five cases displayed elevated AKT1 activation. Among the cases with elevated AKT2, but not PI 3-kinase activity (18 cases), three showed down-regulation of PTEN protein expression. Inhibition of PI 3-kinase/AKT2 by wortmannin or LY294002 induces apoptosis in ovarian cancer cells exhibiting activation of the PI 3-kinase/AKT2 pathway. These findings demonstrate for the first time that activation of AKT2 is a common occurrence in human ovarian cancer and that PI 3-kinase/Akt pathway may be an important target for ovarian cancer intervention.

Adenocarcinoma, Mucinous↗
PubMed2000

Captopril-associated cholestasis complicating the management of pancreatic cancer.

Cholestatic jaundice is a rare complication associated with the use of the angiotensin -converting enzyme inhibitor captopril. The severity of the disease may range from cholestasis on liver histology to overt fulminant hepatic failure. This diagnosis is seldom considered in patients with pancreatic or biliary tract malignancy. We present a patient with unresectable adenocarcinoma of the pancreas whose jaundice decreased slowly over many weeks despite establishment of adequate endoscopic biliary drainage. The presence of captopril-associated cholestasis confounded confirmation of adequate biliary drainage. The absence of observed hepatic bile secretion at duodenoscopy, as seen in this patient, is a previously unreported endoscopic feature of this syndrome.

Adenocarcinoma↗
PubMed2000

Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice.

We have designed a molecule, GFB-111, that binds to platelet-derived growth factor (PDGF), prevents it from binding to its receptor tyrosine kinase, and blocks PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases, and DNA synthesis. GFB-111 is highly potent (IC50 = 250 nM) and selective for PDGF over EGF, IGF-1, aFGF, bFGF, and HRGbeta (IC50 values > 100 microM), but inhibits VEGF-induced Flk-1 tyrosine phosphorylation and Erk1/Erk2 activation with an IC50 of 10 microM. GFB-111 treatment of nude mice bearing human tumors resulted in significant inhibition of tumor growth and angiogenesis. The results demonstrate the feasibility of designing novel growth factor-binding molecules with potent anticancer and antiangiogenic activity.

Angiogenesis Inhibitors↗
PubMed2000

Immunohistochemical profile of endometrial adenocarcinoma: a study of 61 cases and review of the literature.

The differences in immunohistochemical expression of p53, bcl-2, bax, estrogen receptor (ER), and progesterone receptor (PR) were evaluated in 40 endometrioid and 21 papillary serous carcinomas of endometrium and correlated with known predictors of survival, such as grade and stage. Uterine papillary serous adenocarcinomas (UPSA) showed significantly higher p53 expression than did uterine endometrioid adenocarcinomas (UEA) (76.2% versus 35%), whereas both ER and PR were more often positive in endometrioid than in serous tumors (p = .005 and .0005). No significant difference was found in bcl-2 and bax expression between both histologic types. However, there was definite decrease in intensity of bcl-2 in UPSA compared with UEA. In endometrioid carcinoma, p53 overexpression was associated with high-grade and advanced-stage tumors (p = .0006 and .006), whereas ER and PR expression was associated with low-grade and early-stage tumors (p = .0006 and .0001; p = .003 and .0006). Bcl-2 immunopositivity was more common in low-grade, early-stage rather than in high-grade, advanced-stage adenocarcinomas, but the difference was not statistically significant (p = .24 and .07). Bax immunopositivity was associated with well-differentiated (p = .04) and early-stage tumors. Furthermore, a significant inverse relationship between bax and p53 reactivity was defined (p = .05), especially in tumors of endometrioid type. Bax and PR immunoexpression correlated near the limit of statistical significance (p = .08), whereas no relationship was found among bax, bcl-2, and ER immunopositivity. Our results indicate that the differences in immunohistochemical profiles of endometrioid and serous carcinomas support the existence of different molecular pathways of their development. The correlation of immunohistochemical findings with histologic grade and clinical stage could help in predicting biologic behavior and planning treatment in patients who are diagnosed as having these tumors.

Adenocarcinoma↗
PubMed2000

Electrically mediated plasmid DNA delivery to hepatocellular carcinomas in vivo.

Gene therapy by direct delivery of plasmid DNA has several advantages over viral gene transfer, but plasmid delivery is less efficient. In vivo electroporation has been used to enhance delivery of chemotherapeutic agents to tumors in both animal and human studies. Recently, this delivery technique has been extended to large molecules such as plasmid DNA. Here, the successful delivery of plasmids encoding reporter genes to rat hepatocellular carcinomas by in vivo electroporation is demonstrated.

Animals↗
PubMed2000

Chronic esophagitis dissecans presenting with esophageal strictures: a case report.

Chronic esophagitis dissecans superficialis is a rare form of chronic esophagitis producing esophageal cast. Its clinical and histopathologic features have recently been defined. We present a 78-year-old patient with chronic esophagitis dissecans associated with esophageal strictures. The clinical and pathologic features of chronic esophagitis dissecans superficialis are reviewed. The association of chronic esophagitis dissecans superficialis with strictures has not been previously reported.

Aged↗
PubMed2000

Density-dependent growth inhibition of fibroblasts ectopically expressing p27(kip1).

The cyclin/cyclin-dependent kinase (cdk) inhibitor p27(kip1) is thought to be responsible for the onset and maintenance of the quiescent state. It is possible, however, that cells respond differently to p27(kip1) in different conditions, and using a BALB/c-3T3 cell line (termed p27-47) that inducibly expresses high levels of this protein, we show that the effect of p27(kip1) on cell cycle traverse is determined by cell density. We found that ectopic expression of p27(kip1) blocked the proliferation of p27-47 cells at high density but had little effect on the growth of cells at low density whether exponentially cycling or stimulated from quiescence. Regardless of cell density, the activities of cdk4 and cdk2 were markedly repressed by p27(kip1) expression, as was the cdk4-dependent dissociation of E2F4/p130 complexes. Infection of cells with SV40, a DNA tumor virus known to abrogate formation of p130- and Rb-containing complexes, allowed dense cultures to proliferate in the presence of supraphysiological amounts of p27(kip1) but did not stimulate cell cycle traverse when cultures were cotreated with the potent cdk2 inhibitor roscovitine. Our data suggest that residual levels of cyclin/cdk activity persist in p27(kip1)-expressing p27-47 cells and are sufficient for the growth of low-density cells and of high-density cells infected with SV40, and that effective disruption of p130 and/or Rb complexes is obligatory for the proliferation of high-density cultures.

3T3 Cells↗