Incretin-based drugs decrease the incidence of prostate cancer in type 2 diabetics: A pooling-up analysis.

Incretin-based drugs, a class of Antidiabetic medications (ADMs) used in the treatment of type 2 diabetes, may affect the incidence of prostate cancer (PCa). But real-world evidence for this possible effect is lacking. Therefore, the aim of this study is to assess the effect of incretin-based drugs on the incidence of PCa, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. We searched PubMed, Embase, and Cochrane Library databases for eligible studies through September 2023. Two independent reviewers performed screening and data extraction. We used the Cochrane Handbook for Systematic Reviews and the Newcastle-Ottawa Scale (NOS) to assess the quality of included randomized controlled trials (RCTs) and cohort studies. We did a meta-analysis of available trial data to calculate overall risk ratios (RRs) for PCa. A total of 1238 articles were identified in our search. After screening for eligibility, 7 high-quality studies met the criteria for meta-analysis, including 2 RCTs and 5 cohort studies, with a total of 1165,738 patients. Compared with the control group, we found that incretin-based drugs reduced the relative risk of PCa by 35% (95% confidence interval (CI), 0.17-0.49; P = .0006). In subgroup analysis, the RR values for GLP-1 receptor agonists and DPP-4 inhibitors were 62% (95% CI, 0.45-0.85; P = .003) and 72% (95% CI, 0.46-1.12; P = .14), respectively. Incretin-based drugs are associated with lower incidence of prostate cancer and may have a preventive effect on prostate cancer in patients with type 2 diabetes.

Effect of anti-COVID-19 drugs on patients with cancer.

The clinical treatment of patients with cancer who are also diagnosed with coronavirus disease (COVID-19) has been a challenging issue since the outbreak of COVID-19. Therefore, it is crucial to understand the effects of commonly used drugs for treating COVID-19 in patients with cancer. Hence, this review aims to provide a reference for the clinical treatment of patients with cancer to minimize the losses caused by the COVID-19 pandemic. In this study, we also focused on the relationship between COVID-19, commonly used drugs for treating COVID-19, and cancer. We specifically investigated the effect of these drugs on tumor cell proliferation, migration, invasion, and apoptosis. The potential mechanisms of action of these drugs were discussed and evaluated. We found that most of these drugs showed inhibitory effects on tumors, and only in a few cases had cancer-promoting effects. Furthermore, inappropriate usage of these drugs may lead to irreversible kidney and heart damage. Finally, we have clarified the use of different drugs, which can provide useful guidance for the clinical treatment of cancer patients diagnosed with COVID-19.

Diagnostic accuracy of multiparametric ultrasound in the diagnosis of prostate cancer: systematic review and meta-analysis.

OBJECTIVES: Ultrasound (US) technology has recently made advances that have led to the development of modalities including elastography and contrast-enhanced ultrasound. The use of different US modalities in combination may increase the accuracy of PCa diagnosis. This study aims to assess the diagnostic accuracy of multiparametric ultrasound (mpUS) in the PCa diagnosis. METHODS: Through September 2023, we searched through Cochrane CENTRAL, PubMed, Embase, Scopus, Web of Science, ClinicalTrial.gov, and Google Scholar for relevant studies. We used standard methods recommended for meta-analyses of diagnostic evaluation. We plot the SROC curve, which stands for summary receiver operating characteristic. To determine how confounding factors affected the results, meta-regression analysis was used. RESULTS: Finally, 1004 patients from 8 studies that were included in this research were examined. The diagnostic odds ratio for PCa was 20 (95% confidence interval (CI), 8-49) and the pooled estimates of mpUS for diagnosis were as follows: sensitivity, 0.88 (95% CI, 0.81-0.93); specificity, 0.72 (95% CI, 0.59-0.83); positive predictive value, 0.75 (95% CI, 0.63-0.87); and negative predictive value, 0.82 (95% CI, 0.71-0.93). The area under the SROC curve was 0.89 (95% CI, 0.86-0.92). There was a significant heterogeneity among the studies (p < 0.01). According to meta-regression, both the sensitivity and specificity of mpUS in the diagnosis of clinically significant PCa (csPCa) were inferior to any PCa. CONCLUSION: The diagnostic accuracy of mpUS in the diagnosis of PCa is moderate, but the accuracy in the diagnosis of csPCa is significantly lower than any PCa. More relevant research is needed in the future. CRITICAL RELEVANCE STATEMENT: This study provides urologists and sonographers with useful data by summarizing the accuracy of multiparametric ultrasound in the detection of prostate cancer. KEY POINTS: • Recent studies focused on the role of multiparametric ultrasound in the diagnosis of prostate cancer. • This meta-analysis revealed that multiparametric ultrasound has moderate diagnostic accuracy for prostate cancer. • The diagnostic accuracy of multiparametric ultrasound in the diagnosis of clinically significant prostate cancer is significantly lower than any prostate cancer.

Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms: A Randomized Clinical Trial.

Importance: Adenomyosis is a common chronic gynecological disorder, and its treatment is an unmet need. New therapies need to be developed. Mifepristone is being tested for adenomyosis treatment. Objective: To determine whether mifepristone is effective and safe for adenomyosis treatment. Design, Setting, and Participants: This multicenter, placebo-controlled, double-blind randomized clinical trial was conducted in 10 hospitals in China. In total, 134 patients with adenomyosis pain symptoms were enrolled. Trial enrollment began in May 2018 and was completed in April 2019, and analyses were conducted from October 2019 to February 2020. Interventions: Participants were randomized 1:1 to receive mifepristone 10 mg or placebo orally once a day for 12 weeks. Main Outcomes and Measures: The primary end point was the change in adenomyosis-associated dysmenorrhea intensity, evaluated by the visual analog scale (VAS) after 12 weeks of treatment. Secondary end points included the change in menstrual blood loss, increased level of hemoglobin in patients with anemia, CA125 level, platelet count, and uterine volume after 12 weeks of treatment. Safety was assessed according to adverse events, vital signs, gynecological examinations, and laboratory evaluations. Results: In total, 134 patients with adenomyosis and dysmenorrhea were randomly assigned, and 126 patients were included in the efficacy analysis, including 61 patients (mean [SD] age, 40.2 [4.6] years) randomized to receive mifepristone and 65 patients (mean [SD] age, 41.7 [5.0] years) randomized to received the placebo. The characteristics of the included patients at baseline were similar between groups. The mean (SD) change in VAS score was -6.63 (1.92) in the mifepristone group and -0.95 (1.75) in the placebo group (P < .001). The total remission rates for dysmenorrhea in the mifepristone group were significantly better than those in the placebo group (effective remission: 56 patients [91.8%] vs 15 patients [23.1%]; complete remission: 54 patients [88.5%] vs 4 patients [6.2%]). All the secondary end points showed significant improvements after mifepristone treatment for menstrual blood loss, hemoglobin (mean [SD] change from baseline: 2.13 [1.38] g/dL vs 0.48 [0.97] g/dL; P < .001), CA125 (mean [SD] change from baseline: -62.23 [76.99] U/mL vs 26.89 [118.70] U/mL; P < .001), platelet count (mean [SD] change from baseline: -28.87 [54.30]×103/µL vs 2.06 [41.78]×103/µL; P < .001), and uterine volume (mean [SD] change from baseline: -29.32 [39.34] cm3 vs 18.39 [66.46] cm3; P < .001). Safety analysis revealed no significant difference between groups, and no serious adverse events were reported. Conclusions and Relevance: This randomized clinical trial showed that mifepristone could be a new option for treating patients with adenomyosis, based on its efficacy and acceptable tolerability. Trial Registration: ClinicalTrials.gov Identifier: NCT03520439.

Efficacy and Safety of Apatinib for the Treatment of Advanced or Recurrent Cervical Cancer: A Single-Arm Meta-Analysis Among Chinese Patients.

Background: Although various effective compounds for the second- and third-line treatment of advanced or recurrent cervical cancer improved the overall survival, the optimal regimen remains controversial. Previous studies revealed that apatinib had extensive anti-tumor activities. However, almost all studies on apatinib in recurrent cervical cancer are non-randomized controlled trials with small sample sizes, different first-line treatments, and uncontrolled statistical analysis, which may result in a lack of effective metrics to evaluate the efficacy and safety of apatinib. Here, this meta-analysis aims to evaluate the efficacy and safety of apatinib in patients with advanced or recurrent cervical cancer. Methods: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. Results: Seven studies involving 243 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.9% and 68.6%, respectively. With regard to survival analysis, the pooled PFS and OS were 5.19 months and 10.63 months, respectively. The most common treatment-related adverse events of apatinib were hand-foot syndrome (all grade: 39.6%, ≥grade III: 7.5%), hypertension (all grade: 34.5%, ≥grade III: 9.2%), and fatigue (all grade: 28.0%, ≥grade III: 5.1%). Conclusions: In summary, this meta-analysis demonstrated that apatinib has promising efficacy and safety for patients with advanced or recurrent cervical cancer. Systematic Review Registration: https://inplasy.com/inplasy-2022-7-0049/, identifier INPLASY202270049.

"γδT Cell-IL17A-Neutrophil" Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy.

Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2 signaling axis, is commonly used in the clinic for solid tumors. However, antiangiogenic therapies for breast cancer patients have produced limited survival benefits since cancer cells rapidly resistant to anti-VEGFR2 therapy. We applied the low-dose and high-dose VEGFR2 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast cancer mouse models and found that low-dose VEGFR2 mAb or VEGFR2-TKI achieved good effects in controlling cancer progression, while high-dose treatment was not effective. To further investigate the mechanism involved in regulating the drug resistance, we found that high-dose anti-VEGFR2 treatment elicited IL17A expression in γδ T cells via VEGFR1-PI3K-AKT pathway activation and then promoted N2-like neutrophil polarization, thus inducing CD8+ T cell exhaustion to shape an immunosuppressive microenvironment. Combining anti-VEGFR2 therapy with immunotherapy such as IL17A, PD-1 or Ly-6G mAb therapy, which targeting the immunomodulatory axis of "γδT17 cells-N2 neutrophils" in vivo, showed promising therapeutic effects in breast cancer treatment. This study illustrates the potential mechanism of antiangiogenic therapy resistance in breast cancer and provides synergy treatment for cancer.

Insights Into the Prognostic Value and Immunological Role of NAAA in Pan-Cancer.

N-Acylethanolamine Acid Amidase (NAAA) is an N-terminal cysteine hydrolase and plays a vital physiological role in inflammatory response. However, the roles of NAAA in tumor immunity are still unclear. By using a series of bioinformatics approaches, we study combined data from different databases, including the Cancer Genome Atlas, the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Human Protein Atlas, TIMER, and ImmuCellAI to investigate the role of NAAA expression in prognosis and tumor immunity response. We would like to reveal the potential correlations between NAAA expression and gene alterations, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, tumor microenvironment (TME), immune infiltration levels, and various immune-related genes across different cancers. The results show that NAAA displayed abnormal expression within most malignant tumors, and overexpression of NAAA was associated with the poor prognosis of tumor patients. Through gene set enrichment analysis (GSEA), we found that NAAA was significantly associated with cell cycle and immune regulation-related signaling pathways, such as in innate immune system, adaptive immune system, neutrophil degranulation, and Toll-like receptor signaling pathways (TLRs). Further, the expression of NAAA was also confirmed to be correlated with tumor microenvironment and diverse infiltration of immune cells, especially tumor-associated macrophage (TAM). In addition to this, we found that NAAA is co-expressed with genes encoding major histocompatibility complex (MHC), immune activation, immune suppression, chemokine, and chemokine receptors. Meanwhile, we demonstrate that NAAA expression was correlated with TMB in 4 cancers and with MSI in 10 cancers. Our study reveals that NAAA plays an important role in tumorigenesis and cancer immunity, which may be used to function as a prognostic biomarker and potential target for cancer immunotherapy.

Diagnostic Accuracy of Contemporary Selection Criteria in Prostate Cancer Patients Eligible for Active Surveillance: A Bayesian Network Meta-Analysis.

BACKGROUND: Several active surveillance (AS) criteria have been established to screen insignificant prostate cancer (insigPCa, defined as organ confined, low grade and small volume tumors confirmed by postoperative pathology). However, their comparative diagnostic performance varies. The aim of this study was to compare the diagnostic accuracy of contemporary AS criteria and validate the absolute diagnostic odds ratio (DOR) of optimal AS criteria. METHODS: First, we searched Pubmed and performed a Bayesian network meta-analysis (NMA) to compare the diagnostic accuracy of contemporary AS criteria and obtained a relative ranking. Then, we searched Pubmed again to perform another meta-analysis to validate the absolute DOR of the top-ranked AS criteria derived from the NMA with two endpoints: insigPCa and favorable disease (defined as organ confined, low grade tumors). Subgroup and meta-regression analyses were conducted to identify any potential heterogeneity in the results. Publication bias was evaluated. RESULTS: Seven eligible retrospective studies with 3,336 participants were identified for the NMA. The diagnostic accuracy of AS criteria ranked from best to worst, was as follows: Epstein Criteria (EC), Yonsei criteria, Prostate Cancer Research International: Active Surveillance (PRIAS), University of Miami (UM), University of California-San Francisco (UCSF), Memorial Sloan-Kettering Cancer Center (MSKCC), and University of Toronto (UT). I2 = 50.5%, and sensitivity analysis with different insigPCa definitions supported the robustness of the results. In the subsequent meta-analysis of DOR of EC, insigPCa and favorable disease were identified as endpoints in ten and twenty-two studies, respectively. The pooled DOR for insigPCa and favorable disease were 0.44 (95%CI, 0.31-0.58) and 0.66 (95%CI, 0.61-0.71), respectively. According to a subgroup analysis, the DOR for favorable disease was significantly higher in US institutions than that in other regions. No significant heterogeneity or evidence of publication bias was identified. CONCLUSIONS: Among the seven AS criteria evaluated in this study, EC was optimal for positively identifying insigPCa patients. The pooled diagnostic accuracy of EC was 0.44 for insigPCa and 0.66 when a more liberal endpoint, favorable disease, was used. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/prospero/], PROSPERO [CRD42020157048].

Tumor-Associated Macrophages (TAMs): A Critical Activator In Ovarian Cancer Metastasis.

Tumor-associated macrophages (TAMs) that appear in every stage of cancer progression are usually tumor-promoting cells and are present abundantly in the tumor-associated microenvironment. In ovarian cancer, the overall and intratumoral M1/M2 ratio is a relatively efficient TAM parameter for predicting the prognosis of patients, especially for serous tissue type cancer. TAMs exhibit immunological checkpoint modulators, such as the B7 family and programmed death-ligand 1 (PD-L1), and play a key role in the development, metastasis and invasion of ovarian cancer, but the underlying mechanism is barely understood. Ovarian cancer is a severe gynecological malignancy with high mortality. Ovarian cancer-associated death can primarily be attributed to cancer metastasis. The majority of patients are diagnosed with wide dissemination in the peritoneum and omentum, limiting the effectiveness of surgery and chemotherapy. In addition, unlike other well-documented cancers, metastasis through vasculature is not a usual dissemination pathway in ovarian cancer. This review sheds light on TAMs and the main process and mechanism of ovarian cancer metastasis.

The role of Prostate Imaging Reporting and Data System score in Gleason 3 + 3 active surveillance candidates enrollment: a diagnostic meta-analysis.

BACKGROUND: The contemporary active surveillance (AS) criteria may result in an unsatisfactory misclassification rate, which may delay curative treatment for prostate cancer patients. The magnetic resonance imaging (MRI), not included in any AS criteria, provides useful information for prostate cancer diagnosis. Our goal is to evaluate the diagnostic performance of Prostate Imaging Reporting and Data Systems (PI-RADS) score, a standardized MRI reporting system, in AS candidates enrollment. METHODS: We searched Cochrane CENTRAL, PubMed, and Embase for pertinent studies through June 2018. The standard methods recommended for meta-analyses of diagnostic evaluation were employed. We draw the summary receiver operating characteristic (SROC) curve. Meta-regression analysis was performed to evaluate the effects of confounding factors. RESULTS: From the resulting 168 studies, 5 provided the diagnostic data on PI-RADS score and pathological results; 834 patients were included. All AS candidates in these studies were defined by Prostate Cancer Research International: Active Surveillance (PRIAS) criterion. The pooled estimates of PI-RADS 4 or 5 on adverse pathological features at radical prostatectomy (RP) among AS candidates were: sensitivity, 0.77 (95% confidence interval (CI), 0.71-0.82); specificity, 0.63 (95% CI, 0.55-0.71); positive predictive value, 0.72 (95% CI, 0.64-0.79); negative predictive value, 0.68 (95% CI, 0.63-0.73); and diagnostic odds ratio, 6 (95% CI, 4-8). The SROC curve was positioned toward the desired upper left corner of the curve, the area under the curve was 0.77 (95% CI, 0.73-0.80). The P-value for heterogeneity was <0.01. The pathological outcomes and endorectal coils contributed to the heterogeneity of sensitivity. The evidences supporting the advantage of PI-RADS v2 over v1 were not sufficient yet. CONCLUSION: AS candidates with PI-RADS 4 or 5 may be unsuitable for AS even though they fulfill current AS criteria. Those with PI-RADS 3 or less indicated relative safety for AS enrollment.

Contemporary Epstein Criteria with Biopsy-Naïve Multiparametric Magnetic Resonance Imaging to Prevent Incorrect Assignment to Active Surveillance in the PI-RADS Version 2.0 Era.

PURPOSE: The aim of this study is to evaluate the effectiveness of multiparametric magnetic resonance imaging (mp-MRI) in prostate cancer (PCa) patients with biopsy Gleason score ≤ 6 who may otherwise be assigned to active surveillance (AS). PATIENTS AND METHODS: This was a retrospective study of 90 patients who underwent transrectal systematic biopsy for prostate cancer with Gleason score ≤ 6 without neoadjuvant therapy, with radical prostatectomy (RP) conducted between September 2009 and March 2018. All patients underwent prebiopsy mp-MRI. The prostate imaging reporting and data system (PI-RADS) version 2.0 score was evaluated. The correlation between imaging results and pathological findings was analyzed. We established models based on Epstein criteria with or without PI-RADS score and evaluated their ability for screening of potential PCa AS candidates. RESULTS: Among 90 patients, 60 (66.7%) had upgrade (Gleason ≥ 7), 30 (33.3%) had extraprostatic extension, and 9 (10%) had seminal vesicle invasion on RP specimens. The rate of unfavorable disease was 67.8% (61 of 90). On multivariate analysis, independent risk factors for unfavorable disease were prostate-specific antigen density and PI-RADS score. The model based on Epstein criteria with PI-RADS score showed improved integrated discrimination improvement index and was superior to the classical Epstein criteria on decision curve analysis for screening potential prostate cancer AS candidates. CONCLUSIONS: Multiparametric MRI with PIRADS 2.0 provides useful supplementary information to Epstein criteria, and may prevent incorrect assignment to active surveillance.

Prognostic value of systemic inflammatory markers in ovarian Cancer: a PRISMA-compliant meta-analysis and systematic review.

BACKGROUND: The prognostic effect of elevated systemic inflammatory markers, including neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), remains controversial in cancer patients. This meta-analysis was conducted to evaluate the predictive values of these markers for prognoses in ovarian cancer patients. METHODS: Potentially relevant publications in PubMed, ISI Web of Science, and EBSCO were searched. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) for overall survival (OS) and progression-free survival (PFS) were determined using a fixed or random effects model. RESULTS: Ten studies involving 2919 patients were included in this meta-analysis. In multivariate analysis, the group with higher NLR had worse OS (HR = 1.34, 95% CI = 1.16-1.54) and shorter PFS (HR = 1.36, 95% CI = 1.17-1.57) than the control group. Furthermore, PLR values higher than the cut-off were associated with not only poorer OS (HR = 1.97, 95% CI = 1.61-2.40) but also more unfavorable PFS (HR = 1.79, 95% CI = 1.46-2.20). Univariate analysis also indicated the same results. Additionally, subgroup analysis showed that when the cut-off values for NLR and PLR were higher, their predictive effects became stronger. CONCLUSION: This comprehensive meta-analysis suggested that the values of inflammatory markers such as NLR and PLR were associated with ovarian cancer survival. Therefore, inflammatory markers can potentially serve as prognostic biomarkers.

PI-RADS v2 and periprostatic fat measured on multiparametric magnetic resonance imaging can predict upgrading in radical prostatectomy pathology amongst patients with biopsy Gleason score 3 + 3 prostate cancer.

PURPOSE: An underestimated biopsy Gleason score 3 + 3 can result in unfounded optimism amongst patients and cause physicians to miss the window for prostate cancer (PCa) cure. This study aims to evaluate the effectiveness of Prostate Imaging Reporting and Data System (PI-RADS) version 2 as well as periprostatic fat (PPF) measured on multiparametric magnetic resonance imaging (mp-MRI) at predicting pathological upgrading amongst patients with biopsy Gleason score 3 + 3 disease. PATIENTS AND METHODS: A retrospective analysis of 56 patients with biopsy Gleason score 6 PCa who underwent prebiopsy mp-MRI and radical prostatectomy (RP) between November 2013 and March 2018 was conducted. Two radiologists performed PI-RADS v2 score evaluation and different fat measurements on mp-MRI. The associations amongst clinical information, PI-RADS v2 score, different fat parameters and pathologic findings were analyzed. A nomogram predicting upgrading was established based on the results of logistic regression analysis. RESULTS: A total of 38 (67.9%) patients were upgraded to Gleason ≥7 disease on RP specimens. Prostate-specific antigen density (PSAD) (p < .001), positive core (p < .001), single-core positivity (p = .039), PI-RADS score (p < .001), front PPF area (p = .007) and front-to-total ratio (the ratio of front PPF area to total contour area) (p < .001) were risk factors for upgrading. On multivariate analysis, Epstein criteria (p = .02), PI-RADS score >3 (p = .024), and front-to-total ratio (p = .006) were independent risk factors for pathologic upgrading. The AUC value of the nomogram was 0.893 (95% CI, 0.787-0.999). CONCLUSION: The combination of PI-RADS v2 and periprostatic fat measured on mp-MRI can help predict pathologic upgrading amongst patients with biopsy Gleason score 3 + 3 PCa.

Effects of SC-560 in combination with cisplatin or taxol on angiogenesis in human ovarian cancer xenografts.

This study was designed to evaluate the effect of cyclooxygenase-1 (COX-1) inhibitor, SC-560, combined with cisplatin or taxol, on angiogenesis in human ovarian cancer xenografts. Mice were treated with intraperitoneal (i.p.) injections of SC-560 6 mg/kg/day, i.p. injections of cisplatin 3 mg/kg every other day and i.p. injections of taxol 20 mg/kg once a week for 21 days. Vascular endothelial growth factor (VEGF) mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR); microvessel density (MVD) was determined by immunohistochemistry; and prostaglandin E2 (PGE2) levels were determined using ELISA. Expression levels of VEGF mRNA and MVD in treatment groups were inhibited significantly when compared with the control group (p < 0.05 for all), and SC-560 combined with cisplatin displayed a greater reduction in the expression of VEGF and MVD than SC-560 or cisplatin alone (p < 0.05). SC-560 combined with taxol showed a greater inhibition on VEGF mRNA expression than SC-560 or taxol alone (p < 0.05). The level of PGE2 in treatment groups was significantly reduced when compared with the control group (p < 0.01 for all). These findings may indicate that cisplatin or taxol supplemented by SC-560 in human ovarian cancer xenografts enhances the inhibition effect of cisplatin or taxol alone on angiogenesis.

Antitumor properties of taxol in combination with cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on ovarian tumor growth in vivo.

The present study was designed to investigate whether taxol in combination with cyclooxygenase (COX) inhibitors could be superior on inhibitory effect of ovarian cancer growth than taxol alone as drug therapy of mice implanted with human ovarian carcinoma cell line SKOV-3. The animals were treated with 100 mg/ kg celecoxib (a COX-2 selective inhibitor) alone or in combination with 3 mg/kg SC-560 (a COX-1 selective inhibitor) by gavage twice a day, 20mg/kg taxol alone by intraperitoneal (IP) once a week or in combination with celecoxib, or SC-560/celecoxib/taxol for 3 weeks. To test the mechanism of the combination treatment, the index of cell proliferation, expression of cyclin D1, and microvessel density (MVD) in tumor tissues were determined by immunohistochemistry and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. Mean tumor volume in the SC-560/celecoxib/taxol group was first significantly lower than control at day 14 (p < 0.05). In the SC-560/celecoxib/taxol group, the index of cell proliferation and apoptosis and quantification of cyclin D1-postive cells were 6.93%, 69.62%, and 19.14%, respectively, which are statistically significant compared with those of the control group (29.85%, p < 0.001; 32.81% and 36.99%, both p < 0.05). Statistical significance on MVD was observed between the SC-560/celecoxib/taxol (39.57 +/- 4.98) and the control (73.2 +/- 1.96) group (p < 0.001). Our results suggest that the combined antitumor efficacy of taxol and COX inhibitors may be superior to taxol alone as drug therapy against ovarian cancer in mice, and that synergism of the combination treatment in part may be mediated through accelerated apoptosis and suppression of cell proliferation and angiogenesis.

Effect of the combination of a cyclooxygenase-1 selective inhibitor and taxol on proliferation, apoptosis and angiogenesis of ovarian cancer in vivo.

This study was designed to investigate the effects of a cyclooxygenase (COX)-1 inhibitor, SC-560, administered in combination with taxol, on the molecular mechanisms of antitumor efficacy in a SKOV-3 human ovarian carcinoma cell xenograft-bearing mouse model. The mice were treated with 6 mg/kg/day SC-560 by gavage twice every other day and 20 mg/kg taxol by intraperitoneal injection once a week for three weeks. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) mRNA levels of ovarian cancer were detected in the tumor tissues using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), respectively. The index of proliferating and apoptotic cells in the tumor tissues was determined by staining for Ki-67 and using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, respectively. On day 7 after the end of administration, the tumor volume of mice in the combination group was reduced by 55.35% compared with that of the control mice, and the difference was statistically significant (P<0.05). In the combination group, the expression of VEGF, MVD and the cell proliferation index were inhibited significantly, while the apoptotic index was notably increased (all P<0.01, compared with the control group). Our results indicate that the molecular mechanisms of the antitumor efficacy of SC-560 combined with taxol therapy may act in part by inhibiting tumor angiogenesis, reducing cell proliferation and inducing cell apoptosis.

Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on ovarian carcinoma in vivo.

The present study was designed to investigate the combined effects of cyclooxygenase (COX)-1 and COX-2 selective inhibitors on human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 3 mg/kg SC-560 (a COX-1 selective inhibitor) alone, 25 mg/kg celecoxib (a COX-2 selective inhibitor) alone, or SC-560/celecoxib by gavage, twice a day for three weeks. To test the mechanism of inhibition of tumor growth by COX selective inhibitors, the index of proliferating cells in tumor tissues was determined by immunostaining and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. The inhibitory rate on tumor growth in the combination group was 35.54% which is significant statistically compared with that of the control group (P < 0.05). In the combination group, the index of cell proliferation and apoptosis were 12.40% and 51.03% respectively, which are significant statistically compared with those of the control group (22.56%, 19.07%, all P < 0.05). These studies indicate that synergism between two COX inhibitors and inhibitor combination treatment has particular potential for chemoprevention of ovarian cancer growth.

Cyclin D1 expression and the inhibitory effect of celecoxib on ovarian tumor growth in vivo.

The report aims to investigate the relationship between the expression of cyclin D1 and Cyclooxgenase-2 (COX-2), thus to explore the molecular mechanisms of the antitumor efficacy of Celecoxib, a COX-2 inhibitor. Human ovarian SKOV-3 carcinoma cell xenograft-bearing mice were treated with Celecoxib by infusing gaster (i.g.) twice/day for 21 days. The mRNA levels of COX-2 and cyclin D1 were determined by RT-PCR. The expression of cyclin D1 at the protein level was detected by immunohistochemistry, while COX-2 protein expression was determined by Western blot. A high-dose of Celecoxib (100 mg/kg) significantly inhibited tumor growth (P < 0.05), and the expression of cyclin D1 was reduced by 61%. Celecoxib decreased the proliferation cell index by 40% (P < 0.001) and increased apoptotic index by 52% (P < 0.05) in high-dose Celecoxib treated group. Our results suggest that the antitumor efficacy of Celecoxib against ovarian cancer in mice may in part be mediated through suppression of cyclin D1, which may contribute to its ability to suppress proliferation.