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Biomedical subjects

D Coppola

Publications and source records attributed to D Coppola.

At least 37 records · Page 2Linked to original sources
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↗
PubMed2000

Factors affecting morbidity, mortality, and survival in patients undergoing Ivor Lewis esophagogastrectomy.

OBJECTIVES: To examine the safety of transthoracic esophagogastrectomy (TTE) in a multidisciplinary cancer center and to determine which clinical parameters influenced survival and the rates of death and complications. SUMMARY BACKGROUND DATA: Although the incidence of cancer at the gastroesophageal junction has been rising rapidly in the United States, controversy still exists about the safety of surgical procedures designed to remove the distal esophagus and proximal stomach. Alternatives to TTE have been proposed because of the reportedly high rates of death and complications associated with the procedure. METHODS: Data from 143 patients treated by TTE by one author (1989-1999) were entered into a computerized database. Preoperative clinical parameters were tested for effect on death, complications, and survival. RESULTS: The patient population consisted of 127 men and 16 women. One hundred twenty-one patients had a history of tobacco abuse, and 118 reported the regular ingestion of alcohol. One hundred fifteen patients had adenocarcinoma, 16 had squamous cell cancer, 6 had another form of esophageal tumor, and 6 had high-grade dysplasia associated with Barrett epithelia. Fifty-six patients had adenocarcinomas arising in Barrett epithelium. Twenty-eight patients were treated with neoadjuvant chemoradiation before surgery. Three patients died within 30 days of surgery (mortality rate 2.1%). Five patients (3.5%) had a documented anastomotic leak; three died). Overall, 42 patients had complications (29%). Twenty-six had pulmonary complications (19%). The mean length of stay in the intensive care unit was 3.35 days; the mean hospital length of stay was 13.54 days. The overall 3-year survival rate was 29.6%. CONCLUSIONS: A high ASA score and the development of complications predicted an increased length of stay. The presence of diabetes predicted the development of complication and an increased length of stay. None of the other parameters tested predicted perioperative death or complications. Only disease stage, diabetes, and blood transfusion affected overall survival. From these results with a large series of patients with gastroesophageal junction cancers, TTE can be performed with a low death rate (2.1%), a low leak rate (3. 5%), and an acceptable complication rate (29%).

Adenocarcinoma↗
PubMed2000

The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis.

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformation without toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor growth is not well understood. Here, we demonstrate that FTI-277 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated growth factor- and adhesion-dependent survival pathways and induces apoptosis in human cancer cells that overexpress AKT2. Furthermore, overexpression of AKT2, but not oncogenic H-Ras, sensitizes NIH 3T3 cells to FTI-277, and a high serum level prevents FTI-277-induced apoptosis in H-Ras- but not AKT2-transformed NIH 3T3 cells. A constitutively active form of AKT2 rescues human cancer cells from FTI-277-induced apoptosis. FTI-277 inhibits insulin-like growth factor 1-induced PI 3-kinase and AKT2 activation and subsequent phosphorylation of the proapoptotic protein BAD. Integrin-dependent activation of AKT2 is also blocked by FTI-277. Thus, a mechanism for FTI inhibition of human tumor growth is by inducing apoptosis through inhibition of PI 3-kinase/AKT2-mediated cell survival and adhesion pathway.

Alkyl and Aryl Transferases↗
PubMed2000

Esophageal cast: a manifestation of graft-versus-host disease.

Diffuse involvement of the gastrointestinal tract by graft-versus-host disease (GVHD) is a common complication of bone marrow transplantation. The esophageal involvement in this disease tends to be a vesiculobullous, ulcerative or desquamative process. To our knowledge, esophageal cast has not been described in the context of GVHD. However, it has been described as a result of trauma to the esophagus or in association with bullous disease of the skin. We present a case of esophageal cast in a patient with chronic GVHD following bone marrow transplant.

Biopsy↗
PubMed2000

Retinoblastoma protein activation of interleukin 8 expression inhibits tumor cell survival in nude mice.

Loss of retinoblastoma protein (Rb) has been implicated in the formation of a variety of human malignancies. Restoration of Rb expression in the cell lines representing these tumors eliminates or significantly reduces tumorigenicity in nude mice, but the mechanism for this Rb effect is unknown. Results from this study indicated that Rb expression reduced tumor cell survival in nude mice by dramatically enhancing interleukin 8 (IL-8) secretion. IL-8 secreted by the Rb-transformed cells attracted neutrophils in vitro and tumor-infiltrating neutrophils in vivo, which is consistent with the Rb-mediated tumor regression being dependent on IL-8. The apparent, contradictory roles of IL-8 as a protumorigenic and antitumorigenic cytokine are discussed.

Animals↗
PubMed1999

Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo.

Whereas signal transducers and activators of transcription were originally discovered as mediators of normal cytokine signaling, constitutive activation of certain signal transducer and activator of transcription proteins, including Stat3, has been found in increasing numbers of human cancers. Recently, a causal role for Stat3 activation in oncogenesis has been demonstrated, suggesting that Stat3 represents a novel target for cancer therapy. We report here that in vitro expression of a Stat3 variant with dominant-negative properties, Stat3beta, induced cell death in murine B16 melanoma cells that harbored activated Stat3. By contrast, expression of Stat3beta had no effect on normal fibroblasts or the Stat3-negative murine tumor MethA, suggesting that only tumor cells with activated Stat3 have become dependent on this pathway for survival. Significantly, gene therapy by electroinjection of the Stat3beta expression vector into preexisting B16 tumors caused inhibition of tumor growth as well as tumor regression. This Stat3beta-induced antitumor effect is associated with apoptosis of the B16 tumor cells in vivo. These findings demonstrate for the first time that interfering with Stat3 signaling induces potent antitumor activity in vivo and thus identify Stat3 as a potential molecular target for therapy of human cancers harboring activated Stat3.

Animals↗
PubMed1999

The insulin-like growth factor 1 receptor induces transformation and tumorigenicity of ovarian mesothelial cells and down-regulates their Fas-receptor expression.

Cell proliferation and papillogenesis are growth factor-sensitive events in the ovarian mesothelium, the tissue source of ovarian epithelial cancer. To further investigate the regulation of cell proliferation in this tissue, rabbit ovarian mesothelial cells (OMC) were transfected in vitro with a CVN expression vector carrying the human gene for insulin-like growth factor 1 receptor (IGF-1R). The growth characteristics of IGF-1R transfectants (OMIR) and their response to IGF-1 were then compared with those of OMC in serumless HL-1 cultures. OMIR cells formed epithelial-like colonies and, even when nonconfluent, produced tridimensional structures reminiscent of papillae seen in ovarian serous epithelial tumors. After 3 and 7 days of exposure to IGF-1, OMIR cells grew approximately 20-fold (P < 0.05), and papillogenesis was 15- to 25-fold over similar events in OMC, respectively. Exposure to treatment with antisense oligonucleotides against IGF-1R mRNA inhibited OMIR growth rate by 70%. Western immunoblotting and flow cytometry revealed higher expression of IGF-1R in OMIR cells than in OMC. The reverse was true when Fas-receptor expression was evaluated. OMIR cells were clonogenic in 15% serum-rich soft agar assay (OMIR:OMC colony-forming ratio 150-200:1), and tumorigenic in nude mice in which high-grade carcinomas with occasional lung metastases were observed. These data suggest that IGF-1R plays a role in ovarian epithelial carcinogenesis. The overexpression of this receptor induces transformation and morphogenesis of OMCs via an autocrine mechanism. IGF-1R may down-regulate the Fas expression rendering transformed ovarian mesothelial cells resistant to apoptosis.

Animals↗
PubMed1999

Electrically enhanced drug delivery for the treatment of soft tissue sarcoma.

BACKGROUND: Pulsed electric fields have been shown to increase the effectiveness of antineoplastic agents by temporarily increasing the permeability of cell membranes. This type of drug delivery is called electrochemotherapy, and it has been successful in the treatment of patients with cutaneous malignancies in clinical trials. This study focused on determining the applicability of electrochemotherapy to the treatment of soft tissue sarcoma, using an animal model bearing human sarcomas. The antitumor effects of single and multiple electrochemotherapy treatments were investigated using small (250 mm3) and large (4000 mm3) tumors. METHODS: Established tumors were injected with bleomycin, then electric pulses were administered to the tumor site. Animals were followed based on periodic tumor volume determinations, which were used to categorize treatment of each tumor as a complete response, a partial response, stable disease, or progressive disease. Histologic analysis was used to confirm response data. RESULTS: Animals were randomly assigned to one of four different treatment groups. These groups received no treatment, drug only, electric pulses only, or drug combined with electric pulses. A single electrochemotherapy treatment protocol for small tumors resulted in a 100% complete response rate and a 41.7% cure rate. Multiple treatments of small and large tumors resulted in complete response rates of 83.3% and 100%, respectively. These responses were identical to the cure rates. In contrast, tumors in the groups that received no treatment, electric pulses only, and drug only progressed for both single treatment and multiple treatment scenarios, regardless of tumor size. CONCLUSIONS: In this study, a single electrochemotherapy treatment had a strong cytoreductive effect on small tumors that lasted approximately 35 days, until recurrences began. Multiple treatment of small and large tumors resulted in high complete response rates that lasted at least 100 days after treatment. This indicates the feasibility of electrochemotherapy as a modality of limb-preserving treatment for patients with sarcoma of the extremities.

Animals↗
PubMed1999

Expression of insulin-like growth factor-1 receptor in human colorectal cancer.

The activation of the insulinlike growth factor 1/IGF-1 receptor system (IGF1/IGF1-R) has recently emerged as critical event in transformation and tumorigenicity of several murine and human tumors. Expression of IGF1 and of IGF1-R has been demonstrated in normal and neoplastic intestinal cell lines of rats and humans. However, the modulation of IGF1-R expression during the progression from normal colonic mucosa to adenoma, to carcinoma, and to metastasis, has not been evaluated. In this retrospective study, we investigated the expression of IGF1-R in 12 colonic adenomas (AD), 36 primary colorectal adenocarcinomas (CA), and in 27 corresponding metastases (MT). Normal colonic mucosa (N) was adjacent to the CA in 34 cases. Formalin-fixed, paraffin-embedded tissues of each case were immunostained using the avidin-biotin-peroxidase method. We used an anti-IGF1-R rabbit polyclonal antibody (Santa Cruz Biotechnology, CA; dilution 1:100). Positive staining was quantitated by CAS-200. Moderate to strong cytoplasmic immunostaining was observed in 34 of 36 CA (96%), and in 25 of 27 MT (93%). In all of the positive MTs, the intensity of the staining was always strong. In 10 of 12 ADs (83%), only a faint cytoplasmic stain was identified. Normal mucosa when present was negative. Strong IGF1-R positivity correlated with higher grade and higher-stage tumors (P < .01). These data suggest a role of IGF1-R expression during the progression of colorectal adenoma to carcinoma. An increased number of IGF1-R receptors may favor the metastasis of colorectal cancer.

Adenocarcinoma↗
PubMed1999

Activating SRC mutation in a subset of advanced human colon cancers.

The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver. Studies of the mechanism of c-Src regulation have suggested that c-Src kinase activity is downregulated by phosphorylation of a critical carboxy-terminal tyrosine (Tyr 530 in human c-Src, equivalent to Tyr 527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region. We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis. These results provide, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.

3T3 Cells↗
PubMed1999

Barrett's Esophagus and Barrett's Associated Neoplasia: Etiology and Pathologic Features.

BACKGROUND: The incidence of Barrett's esophagus (BE) has been increasing in recent years. Patients with BE have 30- to 125-fold increased risk of developing adenocarcinoma. New techniques allowing early diagnosis, in addition to the identification of markers capable of predicting tumor progression, are needed. METHODS: The authors discuss the diagnostic features of BE and BE-associated neoplasia. RESULTS: BE can exhibit different types of metaplastic mucosa, but only the specialized (intestinal) mucosa has the potential to progress to dysplasia and carcinoma. The problems associated with diagnosing BE and with predicting the behavior of this condition are outlined. CONCLUSIONS: Studies are underway to identify molecular markers capable of predicting which BE patient will progress to carcinoma. Brush cytology and flow cytometry may become useful tools in the early detection of this disease.

Journal Article↗
PubMed1999

[Rehabilitation, using prosthetic implants, in patients with cancer of the oral cavity].

BACKGROUND: The number of patients treated for neoplasms of the oral cavity (by surgery and/or radiotherapy) requiring prosthesis rehabilitation using osteointegrated implants is increasing greatly. The objective of this research is to examine the correlation between prosthesis rehabilitation using osteointegrated implants, radiotherapy and the use of hyperbaric oxygen treatment in order to reduce the risk of osteoradionecrosis. METHODS: Research was carried out on 13 patients with 58 implants. The patients were divided into three sample groups: group A patients underwent radiotherapy (10 implants), group B patients did not undergo radiotherapy (29 implants) and group C patients first underwent radiotherapy and then hyperbaric oxygen treatment (19 implants). The group C patients first underwent hyperbaric oxygen treatment at 2.5 atmospheres. The osteointegrated implants were then applied and hyperbaric oxygen treatment was carried out again over 20-30 postoperative sittings without any other treatment between the sittings. The whole test period lasted 24 months. RESULTS: Only two implants were lost out of the 58 implants and they were in the group that had undergone radiotherapy. CONCLUSIONS: The results show how pre and postoperative hyperbaric oxygen treatment improves the success rate of osteointegrated implants in mandibular areas that had previously undergone radiotherapy. Moreover, the stability of the prostheses that are fixed to the implants is greatly improved compared to conventional methods.

Dental Prosthesis, Implant-Supported↗
PubMed1998

Squamous-cell carcinoma of the pelvis in a giant condyloma acuminatum: use of neoadjuvant chemoradiation and surgical resection: report of a case.

A 60-year-old bisexual male was referred to our institution for management of an unresectable squamous-cell carcinoma of the pelvis arising in a giant condyloma acuminatum. He received neoadjuvant chemoradiation consisting of 5-fluorouracil and mitomycin C with concurrent external beam radiation, followed by posterior pelvic exenteration. The surgical specimen had no residual cancer. In situ hybridization was performed using a human papilloma virus omniprobe for human papilloma virus subtypes 6, 11, 16, 18, 31, 33, and 35. Two years after diagnosis the patient is doing well with no evidence of recurrent disease.

Antibiotics, Antineoplastic↗