Biomedical subjects

John F Boggess

Publications and source records attributed to John F Boggess.

11 recordsLinked to original sources

PubMed2006

Estrogen-receptor-dependent regulation of telomerase activity in human endometrial cancer cell lines.

OBJECTIVES: Given that prolonged exposure to unopposed estrogen is associated with endometrial cancer development and that the promoter region of the catalytic subunit of the telomerase enzyme, hTERT, contains putative estrogen response elements (EREs), we postulated that estrogen-receptor (ER)-mediated induction of telomerase activity may play an important role in endometrial carcinogenesis. METHODS: ER-positive and ER-negative endometrial cancer cell lines were used. ER alpha expression was reconstituted in ER-negative cell lines by transient transfection. Telomerase activity was assayed using a PCR-based telomeric repeat amplification protocol (TRAP) after exposure to estradiol (E2). hTERT mRNA expression was assessed by real-time RT-PCR. Gel shift assays using oligonucleotide probes encoding each ERE and transient expression assays using luciferase reporter plasmids containing varying lengths of the 5' promoter region of the hTERT gene were performed. RESULTS: E2 induced both hTERT gene transcription and telomerase activity in the ER-positive cell lines, but not in the ER-negative cell lines. Transfection of ER alpha into ER-negative cell lines restored E2-induced hTERT gene transcription and telomerase activity. Gel shift assays revealed two EREs in the hTERT promoter that specifically bind to ER alpha. Luciferase assays demonstrated that at least the proximal ERE is responsible for transcriptional activation by ligand-stimulated ER alpha. CONCLUSIONS: Telomerase activity and hTERT mRNA were increased in response to estrogen in an ER alpha-dependent fashion in endometrial cancer cells. Binding of complexed estrogen with ER alpha to the EREs found within the hTERT promoter suggests a possible mechanism for telomerase induction that may facilitate the malignant transformation of hormone-dependent endometrial cells.

Cell Line, Tumor↗

PubMed2005

The PTEN tumor suppressor inhibits telomerase activity in endometrial cancer cells by decreasing hTERT mRNA levels.

OBJECTIVES: Loss of PTEN expression is one of the most prevalent and earliest molecular abnormalities associated with endometrial carcinogenesis. Given that PTEN is often absent and telomerase is overexpressed by endometrial cancers, we hypothesize that PTEN signaling is important in telomerase regulation. METHODS: PTEN expression was reconstituted in the PTEN-null Ishikawa endometrial cancer cells by adenovirus-mediated gene transduction. Cell proliferation was evaluated 12-96 h after infection. Western blot analysis was performed to assess PTEN status and phosphorylated Akt expression. Telomerase activity was determined by the telomeric repeat amplification protocol (TRAP) assay. hTERT mRNA levels were assessed by real-time RT-PCR. Ishikawa cells were also treated with LY294002, a PI3-kinase inhibitor. RESULTS: Infection of Ishikawa cells by replication-defective recombinant adenovirus expressing wild-type PTEN, but not control adenovirus or adenovirus expressing lipid phosphatase defective PTEN GE mutant, inhibited constitutive Akt activation and suppressed proliferation of Ishikawa cells. Infection by wild-type PTEN adenovirus, but not control adenovirus, inhibited telomerase activity 24 h after infection. This inhibition of telomerase activity was parallel to decreased hTERT mRNA levels. LY294002 treatment resulted in dose-dependent inhibition of Akt activation and cellular proliferation. LY294002 suppressed telomerase activity and decreased hTERT transcript levels in a dose-dependent manner. CONCLUSIONS: Our data suggest that PTEN may regulate telomerase activity by a novel mechanism in which inhibition of Akt activation by PTEN leads to decreased hTERT mRNA levels. Thus, loss of PTEN may allow endometrial cells to continue to express high levels of telomerase activity, facilitating the neoplastic transformation of the endometrium.

Adenoviridae↗

PubMed2005

Rapamycin inhibits hTERT telomerase mRNA expression, independent of cell cycle arrest.

OBJECTIVES: Rapamycin and its analogues have been shown to be promising as anti-neoplastic agents but have not been extensively studied in gynecologic malignancies. Our goal was to examine the ability of rapamycin to suppress growth and regulate telomerase activity in cervical and ovarian cancer cell lines. METHODS: Cell proliferation was assessed after exposure to rapamycin. Cell cycle progression was determined by flow cytometry, and apoptosis was evaluated by DNA fragmentation. hTERT mRNA levels were quantified by real-time RT-PCR. Western blot analysis was performed to assess PTEN status, phosphorylated S6 and total S6 expression. RESULTS: Rapamycin inhibited growth of all the cervical cancer cell lines and 3 of the 4 ovarian cancer cell lines in a dose-dependent manner with IC50 values <50 nM. Loss of PTEN protein expression was seen in only one of the cervical cancer cell lines. Rapamycin induced G1 arrest in those cell lines sensitive to its growth inhibitory effects. In all cell lines, rapamycin rapidly inhibited phosphorylation of S6 and resulted in decreased levels of total S6 protein. Treatment with rapamycin reduced hTERT mRNA expression in both rapamycin-sensitive and -resistant cell lines within 24 h. Thus, the effect of rapamycin on hTERT expression was not dependent on its ability to induce G1 cell cycle arrest. CONCLUSIONS: Our data suggest that rapamycin may potentially exert its anti-tumor effects through two independent pathways by G1 cell cycle arrest as well as suppression of telomerase activity by inhibition of hTERT mRNA transcription.

Antibiotics, Antineoplastic↗

PubMed2005

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma.

OBJECTIVE: Endometrial carcinosarcomas are aggressive biphasic neoplasms traditionally treated as a high-grade uterine sarcoma. Epidermal growth factor receptor (EGFR) and HER2/neu (HER2) tyrosine kinases have been implicated in the development and progression of several human cancers and are targets for therapeutic intervention. The aim of this study was to evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. METHODS: Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed endometrial carcinosarcoma were immunostained with commercially available antibodies to EGFR and HER2. Fluorescent in situ hybridization for HER2 gene amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR expression were correlated with several prognostic variables. RESULTS: EGFR expression was identified in the majority of tumors (45/55, 82%). HER2 overexpression (3+) was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11 (20%) cases. EGFR expression and HER2 gene amplification did not show significant correlation with disease progression, disease-free survival or overall survival. The carcinomatous component of tumors more frequently showed HER2 overexpression as compared to the sarcomatous component (25% vs. 4%, P = 0.008). The sarcomatous component of tumors more frequently showed EGFR overexpression as compared to the carcinomatous component (44% vs. 24%, P = 0.04). CONCLUSIONS: EGFR and HER2 appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous and sarcomatous elements of these tumors showed consistent differences in HER2 and EGFR expression patterns supporting biologic differences between these components. Studies evaluating the clinical utility of HER2 or EGFR targeted therapy in these tumors appear warranted.

Aged↗

PubMed2005

The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial.

OBJECTIVE: The purpose of this research was to study the effects on the physiologic pain response of the neonate during circumcision with the use of a gloved human finger. STUDY DESIGN: This was a randomized controlled trial analyzing the effect of non-nutritive sucking (NNS) on pain response during circumcision. Term neonates were randomized to 2 groups. All infants received oral Tylenol and a dorsal penile nerve block (DPNB) before the circumcision. The study group was offered the addition of NNS before the DPNB and throughout the procedure. The primary outcome measured was heart rate during the circumcision. Other variables studied included crying time and salivary cortisol levels. Each circumcision was filmed to calculate pain profile scores using the Premature Infant Pain Profile. Variables were compared using Student t test, chi-square, and Wilcoxon test. A P value of < .05 was considered significant. RESULTS: Forty-four infants met inclusion criteria. Twenty-two infants were randomized to each arm. No difference in mean heart rate during the procedure was apparent. A significant decrease in crying time, 90-minute post-procedure salivary cortisol level, and post-penile clamping pain score was noted in the study group (all P values < .01). CONCLUSION: NNS significantly decreases some elements of measurable physiologic pain response of the neonate during circumcision. This method is a useful and inexpensive addition to DPNB and oral analgesics.

Circumcision, Male↗

PubMed2005

Consolidation therapy with weekly paclitaxel infusion in advanced epithelial ovarian cancer and primary peritoneal cancer: an extended follow-up.

OBJECTIVE: To determine the impact of weekly paclitaxel consolidation on progression-free survival (PFS) of women undergoing treatment for ovarian cancer. METHODS: All women with advanced epithelial ovarian or primary peritoneal carcinoma, treated with paclitaxel consolidation therapy from August 1997 to March 2002, were identified. Patients received weekly paclitaxel infused at a median dose of 80 mg/m(2) (range: 60-80 mg/m(2)) for a maximum of 12 weeks. A chart review was performed to assess disease status and chemotherapy-related toxicities. PFS was calculated from the date of initiation of induction chemotherapy until the date of documented disease recurrence. RESULTS: 31 women received paclitaxel consolidation therapy over the study period (29 stage III and 2 stage IV). 24 women had epithelial ovarian carcinoma and 7 were diagnosed with primary peritoneal carcinoma. The median PFS was 27 months (range: 12-62 months). The overall 2-year survival was 94%, where 17 women (55%) were without evidence of disease and 12 (39%) were alive with disease. The median follow-up was 41 months (range: 15-77 months). Over 337 weeks of consolidation therapy, 1 patient experienced Grade 3 neuropathy and 1 patient developed Grade 3 neutropenia. CONCLUSION: Consolidation therapy with weekly paclitaxel infusion is a well-tolerated regimen that resulted in a median PFS of 27 months in women who obtained a complete clinical response following induction therapy. Given the lack of side effects and the potential for extending the PFS of those treated, a prospective randomized study of weekly paclitaxel should be considered.

Adult↗

PubMed2004

Uterine serous and grade 3 endometrioid carcinomas: is there a survival difference?

BACKGROUND: Serous components within endometrial carcinoma are reportedly poor prognosticators. However, to the authors' knowledge the percentage of tumors which must be comprised of a serous component in order to affect outcome is unknown. The authors compared overall survival (OS) in women with endometrial carcinomas comprised of various percentages of uterine serous carcinoma (USC) with that of women with International Federation of Gynecology and Obstetrics (FIGO) Grade 3 endometrioid carcinoma (G3EC) to determine whether outcomes varied between these two poorly differentiated histologies. METHODS: Data concerning women with either G3EC or USC who were diagnosed between January 1990 and November 2000 were collected retrospectively. Cases were reviewed to confirm diagnosis and estimate the fraction of tumor comprised of USC. Variables assessed included patient age and race, tumor stage, and lymphovascular space invasion. Associations between variables were tested using the Fisher exact test. The Kaplan-Meier method was used to evaluate OS with comparisons performed using the log-rank test. RESULTS: Fifty-two women with G3EC and 87 women with USC were identified. The OS of women with tumors comprised of > 50% USC was found to be significantly worse compared with women with G3EC (hazard ratio [HR] of 2.4; 95% confidence interval [95% CI], 1.2-5.2). Women with USC were more likely to present with extrauterine disease (odds ratio of 2.2; 95% CI, 1.1-4.5). The 5-year survival rate for women with G3EC was 75% compared with 41% for women with tumors that were > 50% USC (P = 0.01). There was a significant trend toward a worse OS in women with even 10% USC compared with women with G3EC. CONCLUSIONS: USC involving > 50% of an endometrial carcinoma was found to be predictive of worse OS compared with the OS of women with G3EC. In patients with early-stage disease, a trend toward a worse prognosis was found to exist when USC comprised even 10% of a tumor. Investigation into the treatment of endometrial carcinoma should include and document tumors with any percentage comprised of USC.

Carcinoma, Endometrioid↗

PubMed2004

Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Eligible: patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. RESULTS: Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n = 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. CONCLUSION C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.

Adult↗

PubMed2004

Association between uterine serous carcinoma and breast cancer.

OBJECTIVE: Endometrial cancer and breast cancer are two common malignancies found in women. As a result of estrogen dependency, an association is thought to exist between these entities. This study was undertaken to determine if the endometrial carcinomas, which develop in women with a history of breast cancer, were more likely to be of the endometrioid or the serous histology, which is generally considered non-estrogen-dependent. METHODS: A retrospective chart review was conducted for the years 1984-2001. All women who were diagnosed at our institution with endometrial carcinoma were identified. The women who also had a prior history of breast cancer were identified and comprise the cohort for this study. Information regarding age at diagnosis, tumor stage, histologic subtype, and tamoxifen exposure were recorded and analyzed. RESULTS: About 1166 women were diagnosed with endometrial cancer during the study period, of whom 54 (4.6%) had a pre-existing diagnosis of breast cancer. Of the 54 women in this study, 41 had tumors of the endometrioid histology and 13 had a tumor of the serous subtype. There was no difference with regards to median age at the time of diagnosis or years of tamoxifen exposure. Women with breast cancer were more likely to develop uterine serous carcinoma (USC) as compared to one of endometrioid histology (OR 2.6; 95% CI 1.29-5.23). CONCLUSIONS: Women with breast cancer who subsequently developed endometrial cancer exhibited a 2.6-fold increased risk of developing a USC as compared to an endometrioid carcinoma. These findings suggest that there may be an underlying genetic predisposition linking breast cancer and USC.

Aged↗

PubMed2003

Weekly paclitaxel infusion as salvage therapy in ovarian cancer.

The majority of women diagnosed with epithelial ovarian cancer will have persistent or recurrent disease after initial treatment. We evaluated response and toxicity in women with advanced stage disease given salvage paclitaxel as a low-dose, weekly infusion. We performed a retrospective review of 22 women with advanced stage epithelial ovarian (19 women) or primary peritoneal carcinoma (3 women) who had received low-dose, weekly paclitaxel salvage therapy. All women had refractory, persistent, or recurrent disease following first-line treatment with paclitaxel and platin chemotherapy. Response and toxicity were assessed. Measurable disease present on physical or radiologic exam and serum carbohydrate antigen-125 levels were used to assess disease response. Overall response rate to low-dose, weekly paclitaxel salvage therapy was 50% (27% complete, 23% partial). Median progression-free interval (PFI) in responders was 27 weeks (range, 14-68 weeks). Stabilization of disease occurred in an additional 27% of patients with a median PFI of 22 weeks (range, 15-89 weeks). No difference in response was detected between the 7 women with platin-sensitive disease and the 15 women with platin-resistant disease (P = 0.19). The median dose of paclitaxel was 80 mg/m2 (range, 60-80 mg/m2). During a total of 325 weeks of paclitaxel treatment (median per patient, 12 weeks; range, 6-49 weeks), 13 treatment delays occurred (hematologic indication, 9; nonhematologic indication, 4). No cases of grade 4 hematologic toxicity, sepsis, or worsening neuropathy were documented. Weekly paclitaxel infusion given as salvage therapy results in significant clinical response, even in women previously treated with paclitaxel. The regimen is well tolerated with no cases of grade 4 neutropenia or worsening neuropathy in our population.

Adult↗

PubMed2003

Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells.

Rapamycin exerts its biological activity by inhibiting the kinase mammalian target of rapamycin (mTOR), which regulates important cellular processes such as control of cell cycle and cell size, translation initiation, and transcription. The ability of rapamycin to inhibit cancer cell proliferation has led to efforts to develop rapamycin and related mTOR inhibitors as anticancer agents. Some investigators have hypothesized that loss of the PTEN tumor suppressor may sensitize tumor cells to the antiproliferative activity of rapamycin because PTEN loss leads to activation of the mTOR pathway. Because PTEN loss is frequent in endometrial cancer, we have characterized the effect of rapamycin in endometrial cancer cells. We show that rapamycin in the nanomolar concentration range exerts a potent growth-inhibitory effect on endometrial cancer cells through induction of cell cycle arrest. This effect is independent of PTEN status because PTEN-positive ECC-1 cells are as sensitive to rapamycin as PTEN-null Ishikawa and Hec-1B cells, suggesting that rapamycin may be effective against a broad range of endometrial cancers. We also show that rapamycin rapidly inhibits telomerase activity by decreasing the mRNA level of hTERT, the catalytic subunit of telomerase. This implies that rapamycin leads to inhibition of hTERT gene transcription. We demonstrate that rapamycin inhibits phosphorylation of downstream targets of mTOR such as p70(S6K) kinase and 4E-BP1 translation repressor. This work suggests that rapamycin is a potentially useful targeted therapy for endometrial cancer and that loss of telomerase activity may be a good surrogate biomarker for assessing antitumor activity of rapamycin.

Antibiotics, Antineoplastic↗