Biomedical subjects

Mack N Barnes

Publications and source records attributed to Mack N Barnes.

31 records · Page 2Linked to original sources

PubMed2003

Expression of CEA, Tag-72, and Lewis-Y antigen in primary and metastatic lesions of ovarian carcinoma.

Ovarian carcinoma has a high mortality rate, because most ovarian carcinomas are detected at a late stage. Traditional therapies, such as surgical debulking and chemotherapy, have not been successful in improving the long-term survival of these patients. Alternative therapies targeting various biomarkers, such as carcinoembryonic antigen (CEA), Tag-72, and Lewis-Y antigen, have been developed to treat patients with advanced ovarian cancers. To ensure that therapies targeting these biomarkers are effective, it is imperative to determine whether there is any differential expression of these targeted biomarkers between primary and metastatic ovarian carcinomas. In the present study, primary and metastatic lesions from 68 and 58 patients, respectively, including primary and matched metastatic lesions from 31 patients, were evaluated for cytoplasmic and membranous expression of CEA (clone Col-1), Tag-72 (clone CC-49), and Lewis-Y antigen (clone BR-96) by immunohistochemistry. No significant differences were observed with cytoplasmic and membranous expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) in the primary and metastatic, matched and unmatched lesions (Wilcoxon signed-rank test). Although there was no statistically significant difference in the scores of CEA (Col-1) between primary and metastatic lesions, 5 of 11 (45%) cases with positive staining with CEA (Col-1) demonstrated discordant results between primary and metastatic lesions. There was a moderate positive correlation of the cytoplasmic and membranous expression of Tag-72 (CC-49), as well as cytoplasmic expression of BR-96 between primary and metastatic ovarian carcinomas. There was a weak negative correlation between the membranous expression of CEA (Col-1) and that of Lewis-Y antigen (BR-96); however, the difference was not statistically significant. No correlation was observed with other combinations of biomarkers. Our findings suggest that samples from either primary or metastatic ovarian carcinomas can be used for the evaluation of the expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) to identify targets for novel therapies in patients with disseminated ovarian carcinomas. CEA (Col-1), due to its low expression and variation in phenotypic expression between primary and metastatic lesions, should be evaluated carefully in metastatic lesions before targeting the CEA antigen with CEA (Col-1)-like antibodies.

Adenocarcinoma↗

PubMed2003

Primary extrarenal rhabdoid tumor of the ovary. A case report.

BACKGROUND: Malignant rhabdoid tumors are rare, aggressive neoplasms that consist of both renal and extrarenal subtypes. Although extrarenal rhabdoid tumors have been documented at multiple extrarenal sites, to our knowledge no primary ovarian cases have been reported. CASE: An 18-year-old, Caucasian woman was diagnosed with a pure primary extrarenal rhabdoid tumor of the ovary following diagnostic laparoscopy for pelvic pain. The tumor exhibited rapid growth, failed to respond to chemotherapy and led rapidly to death. CONCLUSION: Although no other reports on primary ovarian extrarenal rhabdoid tumor have been published, the aggressive behavior of the tumor in this patient was similar to that seen in patients with metastatic disease.

Adolescent↗

PubMed2002

In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus.

BACKGROUND: Adenovirus-based gene therapy is a promising approach to treat advanced cancers that are resistant to other treatments. However, many primary cells lack the requisite coxsackie-adenovirus receptor (CAR), limiting the in vivo efficacy of gene therapy. Recently, a modified adenovirus that is not dependent on CAR expression for infectivity was developed. We used noninvasive imaging to investigate the in vivo antitumor efficacy of gene therapy using this adenovirus in an animal model of ovarian cancer. METHODS: The adenoviral vectors RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes simplex virus thymidine kinase (TK) for molecular chemotherapy and the human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were established from highly aggressive SKOV3.ip1 cells in immune-deficient mice. Adenoviral constructs were infected intratumorally or intraperitoneally once a day for 3 days. Control mice received three injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector that includes a luciferase marker gene. The somatostatin analogue (99m)Tc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that was injected into subcutaneous tumors. For mice with peritoneal tumors, survival was compared among the different treatment groups using Kaplan-Meier analysis with the log-rank statistic. All statistical tests were two-sided. RESULTS: Tumor-associated RGDTKSSTR could be detected 15 days after introduction of the vector. In the subcutaneous model, tumors injected with RGDTKSSTR were statistically significantly smaller than those injected with AdTKSSTR (P<.001). In the intraperitoneal model, mice treated with RGDTKSSTR lived longer (survival at day 45 = 63.6%; 95% confidence interval [CI] = 35.2% to 92.0%) than those treated with AdTKSSTR (survival at day 45 = 0%) or Ad5Luc1 (survival at day 45 = 18.1%; 95% CI = 0.0% to 41.0%). DISCUSSION: RGDTKSSTR shows antitumor efficacy against ovarian cancer in vivo in animal models. The virus can be imaged noninvasively and may have the potential to be a useful agent for treating ovarian cancer.

Adenoviridae↗

PubMed2002

Treatment of ovarian cancer with a tropism modified oncolytic adenovirus.

Ad5-Delta 24RGD is an adenovirus that is selectively replication competent in cells defective in the Rb/p16 pathway, such as ovarian cancer cells. The fiber of Ad5-Delta 24RGD contains an integrin binding RGD-4C motif, allowing Coxsackie adenovirus receptor-independent infection of cancer cells. Oncolysis of cell lines was similar to that of a wild-type control, and replication in primary tumor material was shown using a novel three-dimensional spheroid model. Finally, an orthotopic murine model of peritoneally disseminated ovarian cancer was used to test i.p. administration to tumor-bearing animals. Injection of the agent resulted in eradication of i.p. disease, whereas control animals expired (P < 0.0001). These results suggest that Ad5-Delta 24RGD could be useful for treatment of ovarian cancer in humans.

Adenoviridae↗

PubMed2002

A pilot study of ovarian cancer chemoprevention using medroxyprogesterone acetate in an avian model of spontaneous ovarian carcinogenesis.

OBJECTIVE: Our previous studies have documented the feasibility of using the laying hen, Gallus domesticus, as a model of spontaneous ovarian carcinogenesis. This study was performed to determine the ability of medroxyprogesterone acetate (Depo-Provera) to reduce the frequency of spontaneously developing reproductive tract adenocarcinoma in the avian model. METHOD: Four hundred 3-year-old hens were in a two-arm trial designed to determine the frequency of epithelial reproductive tract adenocarcinomas. Animals were designated to receive three injections of 100 mg Depo-Provera versus no injection over a 16-month period. Both groups were subjected to two induced molts 12 months apart. Egg counts were obtained and decreased egg production was documented in the treated hens due to Depo-Provera. At the end of 16 months surviving animals were sacrificed and the frequency of reproductive tract adenocarcinoma was determined histologicically. RESULTS: Histologic information was obtained from the 293 hens that completed the full prescribed course of study. At the time of necropsy, multiple hens had evidence of carcinomatosis and massive ascites consistent with metastatic reproductive tract adenocarcinomas. Of the tissues examined from the informative cases gathered at the time of sacrifice, there was evidence of a reduction of reproductive tract adenocarcinoma observed in the Depo-Provera group (45/127-35%) when compared to the control group (69/166-42%). A risk reduction of 15% is observed in the treatment group (risk ratio 0.85: 95% confidence interval 0.63-1.15). CONCLUSION: The high rate of reproductive tract adenocarcinoma observed in this study supports the avian hen as a valid model of spontaneous ovarian carcinogenesis in which to test chemoprevention strategies and provides a unique opportunity for investigating the pathogenesis of ovarian carcinoma. The current histologic findings are consistent with the theory that a reduction of ovulatory events may prevent the development of ovarian adenocarcinoma.

Adenocarcinoma↗

PubMed2002

Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses.

Adenovirus serotype 5 (Ad5) displays unparalleled gene transfer efficacy to cells with high coxsackie-adenovirus receptor (CAR) expression. Unfortunately, cells isolated from clinical human cancers, both ovarian and other types, express highly variable and often low levels of CAR. Fortunately, native Ad5 tropism can be modified to circumvent CAR deficiency and to enhance infectivity. Ad5/3luc1 incorporates the serotype 3 fiber knob and binds to a receptor distinct from CAR, while the fiber of Ad5lucRGD is modified with an RGD-4C motif, allowing CAR-independent binding to integrins. We studied the liver tropism and blood clearance of these viruses after intravenous (i.v.) injection, and biodistribution after intraperitoneal (i.p.) injection to tumor-bearing mice. To estimate efficacy, we assessed gene transfer to purified human primary ovarian cancer cells, and in a mouse model of ovarian cancer. Ad5/3luc1 achieved improved gene transfer over Ad5lucRGD, and both infectivity-enhanced viruses were superior to the isogenic control with an unmodified Ad5 capsid. In the presence of malignant ascites, gene transfer was improved with both Ad5/3luc1 and Ad5lucRGD. Thus, retargeting to the Ad3 receptor enhances gene transfer to clinically relevant ovarian cancer substrates, while the mouse toxicity and biodistribution profile of both fiber-modified Ad vectors is comparable to Ad5.

Adenoviridae↗

PubMed2002

Gene therapy.

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Adjuvants, Immunologic↗

PubMed2002

Effects of nonsteroidal anti-inflammatory agents (NSAIDs) on ovarian carcinoma cell lines: preclinical evaluation of NSAIDs as chemopreventive agents.

PURPOSE: Nonsteroidal anti-inflammatory agents may inhibit carcinogenesis in specific tissues including the colon, breast, and pancreas, and, hence, may prove to be effective chemopreventive agents. The purpose of this study was to investigate the cellular effects of acetylsalicylic acid (ASA), acetaminophen, and a COX-2 inhibitor (NS-398) on the growth of cell lines of human ovarian cancer in vitro. EXPERIMENTAL DESIGN: SK-OV-3, Caov-3, and NIH:OVCAR-3 ovarian carcinoma cell lines were treated with ASA (10(-6) M-10(-2) M), acetaminophen (10(-6) M-10(-2) M), and a COX-2 inhibitor (10(-6) M-10(-4) M) for 96 h. The number of viable cells was determined using a tetrazolium conversion assay. Immunohistochemical assessment was performed for alterations in expression of Ki-67, erbB-2, COX enzyme, and apoptosis in primary ovarian cancer cells using terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay. RESULTS: A decrease in cell number compared with controls was observed for all of the cell lines treated with ASA, acetaminophen, and COX-2 inhibitor by cell count and tetrazolium conversion assay. A significant decrease in Ki-67 compared with controls in the OVCAR-3 (P = 0.005) and SK-OV-3 (P = 0.007) cell lines after treatment with the COX-2 inhibitor was observed. We observed a decrease in mitotic activity compared with controls in each cell line after treatment with the COX-2 inhibitor. Apoptosis was observed in primary ovarian cancer cell culture treated with COX-2 inhibitor. CONCLUSION: Our results suggest additional study for the use of nonsteroidal anti-inflammatory agents, specifically COX-2 inhibitors, as a strategy of chemoprevention for ovarian cancer.

Acetaminophen↗

PubMed2002

Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells.

Gene delivery efficiency in clinical cancer gene therapy trials with recombinant adenoviruses (Ads) based on serotype 5 (Ad5) has been limited partly because of variable expression of the primary Ad5 receptor, the coxsackie and adenovirus receptor (CAR), on human primary cancer cells. As a means of circumventing CAR deficiency, Ad vectors have been retargeted by creating chimeric fibers possessing knob domains of alternate Ad serotypes. In this study, we have constructed an Ad5-based vector, Ad5/3luc1, with a chimeric fiber protein featuring a knob domain derived from Ad3. This virus is retargeted to the Ad3 receptor and, therefore, has different tissue tropism. A novel knob binding assay was used to measure expression of CAR and the Ad3 receptor. Further, to evaluate the correlation of receptor expression and infectivity by Ad, a panel of ovarian cancer cell lines and purified primary cancer cells were infected with Ad5luc1 and Ad5/3luc1 at 50, 200, and 1000 viral particles/cell. Our results confirm that Ad5/3luc1 is retargeted to the Ad3 receptor. Furthermore, the Ad3 receptor is present at higher levels than CAR on ovarian adenocarcinoma cells. Also, the amount of binding to primary receptor appears to be the major factor determining the efficiency of transgene expression. The Ad5/3 chimera displays enhanced infectivity for ovarian cancer cell lines and purified primary tumor cells, which could translate into increased efficacy in clinical trials.

Adenocarcinoma↗

PubMed2002

A Phase I study of combined modality (90)Yttrium-CC49 intraperitoneal radioimmunotherapy for ovarian cancer.

PURPOSE: The purpose of this study was to determine the feasibility and maximum tolerated dose of (90)Yttrium-CC49 ((90)Y-CC49) as the radioimmunotherapy (RIT) component of an i.p. combined modality treatment for recurrent ovarian cancer. EXPERIMENTAL DESIGN: A Phase I trial of (90)Y-CC49 RIT was conducted in ovarian cancer patients who had persistent or recurrent intra-abdominal disease, had failed one or two prior chemotherapy regimens, and demonstrated TAG-72 expression. Patients were treated with a previously established combined modality treatment protocol of s.c. IFN alpha2b, i.p. paclitaxel, and increasing dosages of i.p. (90)Y-CC49. Patients were monitored for toxicity, generation of human antimouse antibody response, and clinical efficacy. RESULTS: Twenty eligible patients were treated per study specifications. All patients had been treated with debulking and paclitaxel/carboplatin-based chemotherapy at initial diagnosis. The patients included 11 patients with persistent disease at the time of second look laparotomy and 9 patients with delayed recurrence. Patients were treated with i.p. (90)Y-CC49 given in combination with s.c. IFN alpha2b (dose of 3 x 10(6) units for a total of four doses) and i.p. paclitaxel (dose of 100 mg/m(2)). RIT treatment was associated with primarily hematological toxicity. The maximum tolerated dose of i.p. (90)Y-CC49 was established at 24.2 mCi/m(2) in this combined regimen. Of nine patients with measurable disease, two had partial responses lasting 2 and 4 months. Of 11 patients with nonmeasurable disease, median time to progression was 6 months in 7 patients who recurred; 4 of these patients remain no evidence of disease at 9+, 18+, 19+, and 23+ months. CONCLUSIONS: (90)Yttrium-CC49-based RIT in combination with IFN alpha2b and i.p. paclitaxel is feasible and well tolerated at a dose of < or =24.2 mCi/m(2).

Adenocarcinoma↗

PubMed2002

Conditionally replicative adenoviruses for ovarian cancer therapy.

The purpose of this review article is to present a logical rationale for the investigation of conditionally replicative adenoviral vectors for the treatment of ovarian carcinoma. A medline database search was performed to identify relevant articles in the English language for the years 1966 to present. The key words used included replicative adenovirus, conditionally replicative adenovirus, transcriptional targeting, replication selective adenovirus, and "ONYX." A total of 89 references were identified and reviewed. Each reference was reviewed for relevance to clinical translation of conditionally replicative adenoviral vector therapy for ovarian cancer. Data from current clinical trials would suggest that potential obstacles for effective replicative viral therapy of ovarian carcinoma include efficient tumor cell infection, restrictions of the cell surface coxsackie and adenovirus receptor, rapid clearance of vector in the ascites environment, tumor cells specificity, and limitations of current findings of clinical trials. The articles were, therefore, evaluated and included if they addressed these shortcomings. Current data would suggest that advanced generation conditionally replicative adenoviral vectors will soon be available for clinical trials in ovarian cancer. Ovarian cancer, because of expression of targetable receptors, transducible cells, and containment within the i.p. cavity, represents a solid tumor suited uniquely for investigation with advanced generation conditionally replicative adenoviral vectors.

Adenoviridae↗

PubMedDate not supplied

p53 and erbB-2 are not associated in matched cases of primary and metastatic ovarian carcinomas.

Ovarian cancer has a high mortality rate largely due to the limited number of ovarian carcinomas detected at an early stage. Understanding the molecular changes occurring during the progression of ovarian carcinoma would aid in the development of therapies that may inhibit or target metastasis. Primary and metastatic lesions from 54 and 40 patients with advanced ovarian carcinoma, respectively (including matched primary and metastatic lesions from 30 patients) were evaluated for nuclear accumulation of p53 (clone BP53-12-1) and cytoplasmic and membranous immunostaining of p185 erbB-2 (clone 3B5) by immunohistochemistry. No differences in the immunostaining of p53 and p185erbB-2 (cytoplasm or membrane) were observed between primary and metastatic lesions of the matched cases. Similarly, no differences in the proportion of positive cases of p53 between primary and metastatic lesions of the matched cases was observed. Thus, novel therapies that target p53 or p185erbB-2 can utilize specimens from either primary or metastatic lesions to characterize these targets prior to therapy. Spearman correlations between p53 and p185erbB-2 (cytoplasm or membrane) immunohistochemistry scores were insignificant for the matched cases, all primary lesions, and all metastatic lesions. Also, no significant associations occurred between nuclear accumulation of p53 (positive versus negative) and phenotypic expression of p185erbB-2 (cytoplasm or membrane) immunostaining scores for the matched cases, all primary lesions, and all metastatic lesions. Thus, the nuclear accumulation of p53 and immunostaining of p185erbB-2 in the cytoplasm or on the cellular membranes are independent.

Biomarkers, Tumor↗

PubMedDate not supplied

Paradigms for primary prevention of ovarian carcinoma.

OBJECTIVE: To provide the clinician with current concepts regarding prevention of ovarian cancer. Specifically, in this review, we provide a rationale for chemoprevention of ovarian cancer, a description of promising chemopreventive agents, and an overview of surgical strategies used in the prevention of ovarian cancer. DATA SOURCES: A computerized search of articles published through December 2001 was performed using the MEDLINE database from the period of 1966 to present. Search terms utilized included ovarian neoplasms, primary prevention, chemoprevention, oral contraceptives, NSAIDs, retinoids, ovariectomy, and tubal sterilization. Additional sources were identified through cross-referencing. METHODS OF STUDY SELECTION: All identified references relevant to prevention of ovarian carcinoma were reviewed. TABULATION, INTEGRATION, AND RESULTS: Each reference was reviewed to determine the relevant contribution to the fundamental science of ovarian cancer prevention. Particular attention was paid to those studies that offered insight into the development of translational trials in ovarian cancer chemoprevention. CONCLUSIONS: Investigation into chemoprevention for ovarian cancer represents a vastly underdeveloped area of research. Continued research efforts toward identification of novel compounds will accelerate the progress of clinical trials in this neglected area of investigation.

Anti-Inflammatory Agents, Non-Steroidal↗