Anticancer Impact of Nitric Oxide (NO) and NO Combination with SMYD-3 Inhibitor on Breast Carcinomas

Despite enormous advances in the detection and treatment of breast cancer, it still remains the leading cancer diagnosis and has the second highest mortality rate. Thus, breast cancer research is a high priority for academics and clinicians alike. Based on previous research indicating the potential of nitric oxide (NO) and SMYD-3 inhibition, this work sought to expand upon these concepts and combine the two approaches. Both NO (from S-Nitrosoglutathione (GSNO)), termed Group 1, and a combination therapeutic, inhibitor-4 (SMYD-3 inhibitor) plus NO (from GSNO), termed Group 2, were evaluated for their efficacy on breast carcinoma cell lines MCF7 and MDA-MB-231, and the normal MCF10A breast cell line, using cellular viability, colony formation capacity, cytotoxicity, and cellular apoptosis analysis. These results indicated that, in Group 1, breast carcinoma lines MCF7 and MDA-MB-231, cells experienced a moderate reduction in cellular viability (~20–25%), a large reduction in colony formation capacity (~80–90%), a moderate increase in the relative number of dead cells, and a moderate increase in cellular apoptosis. Group 2 was significantly more impactful, with a ~50% knockdown in cellular viability, a 100% reduction in colony formation capacity, a large increase in the relative number of dead cells, and a large increase in cellular apoptosis. Additionally, Group 2 induced a very small impact on the normal MCF10A cell line. Cumulatively, this work revealed the exciting impact of this combination therapeutic, indicating its potential for clinical application and further research.

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Immediate and long-term results of the first line chemotherapy in patients with metastatic triple negative breast cancer. Final analysis of randomized study

HEALTH OF WOMAN ◽

10.15574/hw.2020.149.75 ◽

2020 ◽

pp. 75-80

Author(s):

S.A. Lyalkin ◽

◽

L.A. Syvak ◽

N.O. Verevkina ◽

◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Randomized Study ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Group 2 ◽

Line Chemotherapy ◽

Group 1

The objective: was to evaluate the efficacy of the first line chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Materials and methods. Open randomized study was performed including 122 patients with metastatic TNBC. The efficacy and safety of the first line chemotherapy of regimens АТ (n=59) – group 1, patients received doxorubicine 60 мг/м2 and paclitaxel 175 мг/м2 and ТР (n=63) – group 2, patients received paclitaxel 175 мг/м2 and carboplatin AUC 5 were evaluated. Results. The median duration of response was 9.5 months (4.5–13.25 months) in patients received AT regimen and 8.5 months (4.7–12.25 months), in TP regimen; no statistically significant differences were observed, р=0.836. The median progression free survival was 7 months (95% CI 5–26 months) in group 1 and 7.5 months (95% CI 6–35 months) in group 2, p=0.85. Both chemotherapy regimens (AT and TP) had mild or moderate toxicity profiles (grade 1 or 2 in most patients). No significant difference in gastrointestinal toxicity was observed. The incidence of grade 3–4 neutropenia was higher in patients of group 2 (TP regimen): 42.8% versus 27% (р<0.05). Conclusions. Both regimens of chemotherapy (AT and TP) are appropriate to use in the first line setting in patients with metastatic TNBC. Key words: metastatic triple negative breast cancer, chemotherapy, progression free survival, chemotherapy toxicity.

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Endothelial function status in hypogonadal men

Diabetes Mellitus ◽

10.14341/dm12780 ◽

2022 ◽

Vol 24 (5) ◽

pp. 440-447

Author(s):

I. A. Khripun ◽

S. V. Vorobyev

Keyword(s):

Nitric Oxide ◽

Endothelial Function ◽

Adhesion Molecules ◽

Sex Hormones ◽

Carotid Arteries ◽

Secretory Activity ◽

Total Testosterone ◽

Vasomotor Function ◽

Group 2 ◽

Group 1

Background: Type 2 diabetes mellitus (T2DM) and hypogonadism are mutually aggravating diseases associated with the development and progression of cardiovascular pathology. The status of endothelial function in men with T2DM and hypogonadism hasn’t been studied.Aims: To assess the effect of hypogonadism on endothelial function in men with T2DM.Materials and methods: Patients underwent clinical studies, assessment of carbohydrate and lipid metabolism, the content of sex hormones (total testosterone (T), sex hormones binding globulin, free T, luteinizing hormone) and markers of endothelial function (nitric oxide (NO), endothelial nitric oxide synthase type 3 (eNOS3), endothelin, adhesion molecules ICAM-1, VCAM-1, p- and e-selectins, cadherin), ultrasound examinations of endothelium-dependent vasodilation (EDVD) of the brachial artery (BA) and carotid arteries with an assessment of the thickness of intima-media complex (TIM) were performed.Results: The study included 276 men with T2DM (age 54.0[49;60] years), who were divided into 2 groups: 1–124 patients with hypogonadism; 2–152 eugonadal patients. Reduction of the endothelial vasomotor function was detected in 32.4% of patients in the 2st group and in 55.3% of the 1nd group (χ2=6.1; p=0.01), which was associated with a decrease in EDVD by 29.8 % (p<0.001) and an increase in the time of development of maximal BA vasodilation by 30 seconds in patients with hypogonadism (p<0.001). The TIM of the carotid arteries was 10% more in group 1 compared with group 2 (p=0.03). The level of NO in the 1st group was reduced by 1.6 times (p=0.001), eNOS3–by 1.5 times (p=0.038) compared with the 2nd group. The concentrations of adhesion molecules were higher in group 1 compared to group 2: VCAM-1 by 32.5% (p<0.001), ICAM-1 by 43.5% (p<0.001), p-selectin–by 19.3% (p=0.004), cadherin–6 times (p<0.001).Conclusion: Hypogonadism in men with T2DM is associated with the development of endothelial dysfunction, which manifests in a weakening of the EDVD and a slowdown in its development, as well as disturbances of the secretory activity of endothelium–a decrease in NO synthesis and activation of the adhesion molecules expression, which can be regarded as an universal pathogenetic mechanism of the development of cardiovascular diseases in combination of T deficiency and T2DM.

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Comparison of Rare Types of Breast Cancer

Journal of Cancer and Tumor International ◽

10.9734/jcti/2021/v11i230146 ◽

2021 ◽

pp. 9-17

Author(s):

Osman Erdogan ◽

Alper Parlakgumus ◽

Ugur Topal ◽

Kemal Yener ◽

Umit Turan ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Radical Mastectomy ◽

Treatment Modalities ◽

Breast Carcinomas ◽

Term Survival ◽

Prognostic Features ◽

Group 3 ◽

Group 2 ◽

Group 1

Aims: Mucinous, medullary, and papillary carcinomas are rarely encountered types of breast cancer. This study aims to contribute to the literature by comparing the clinical and prognostic features and treatment alternatives of rare breast carcinomas. Study Design: Thirty-four patients with rare breast cancer out of a total of 1368 patients who underwent surgery for breast cancer in our clinic between January 2011 and December 2020 were included in the study. Methodology: The patients were assigned into three groups, i.e., medullary carcinoma group (Group 1), mucinous carcinoma group (Group 2) and papillary carcinoma group (Group 3). Demographic and clinical features, treatment modalities used, surgical approaches, pathological features of tumors and survival were compared between the groups. Results: Thirty-four patients were included in the study. The mean age of the patients in Group 3 was higher, though it was not statistically significant. Modified radical mastectomy was more frequently performed in all the groups. The number of the lymph nodes removed through axillary dissections and the number of the positive lymph nodes were similar in all the groups. The tumors in all the groups were also of comparable sizes (30 mm in Group 1, 42.5 mm in Group 2 and 30 mm in Group 3; p:0.464). Estrogen receptors were negative in a significantly higher rate of Group 1(66.7% of Group 1, p<0,001). A significantly higher rate of Group 1 received postoperative chemotherapy (93,3% of Group 1,p:0.001), but the rate of the patients receiving hormonotherapy in this group was significantly lower (26.7% of Group, p<0,001). The patients with medullary cancer had significantly longer survival than those with mucinous cancer and those with papillary cancer (76.2 in Group 1, 54.5 in Group 2 and 58.4 in Group 3; p:0.005). Conclusion: While rare subtypes of breast carcinoma did not affect opting for surgical treatment, selection of oncological therapy was affected depending on the hormone receptor status of these tumors. The long-term survival differed between rare breast tumors. In view of the unique clinical pictures of the tumors, the patients should be evaluated individually, and the evaluation should be associated with theevidence-based principles available for more common breast carcinomas.

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Prognostic Effects of Local Recurrence after Conservative Treatment for Early Infiltrating Breast Carcinoma

Tumori Journal ◽

10.1177/030089160208800505 ◽

2002 ◽

Vol 88 (5) ◽

pp. 376-378 ◽

Cited By ~ 4

Author(s):

Alfredo Carlos SD Barros ◽

Luis Carlos Teixeira ◽

Antonio Carlos Nisida ◽

Marianne Pinotti ◽

José Aristodemo Pinotti

Keyword(s):

Breast Carcinoma ◽

Local Recurrence ◽

Distant Metastases ◽

Average Period ◽

Logrank Test ◽

Poor Prognostic Factor ◽

Free Survival ◽

Kaplan Meier ◽

Group 2 ◽

Group 1

Aim A study was carried out to determine whether local recurrence after quadrantectomy, axillary dissection and radiotherapy (QUART) affects the oncologic prognosis of patients with early infiltrating breast carcinoma. Methods A total of 149 patients were submitted to QUART between 1981 and 1990 and followed by an average period of 120.9 months (range, 16–213). Local recurrence was not observed in 132 cases (group 1) but was detected in 17 patients (group 2). Results In group 1, 39 cases (29.5%) presented distant metastases and 34 (25.8%) evolved to death. In group 2, 10 (51.8%) distant metastases and 9 deaths (52.9%) were verified. The survival curves estimated by the Kaplan-Meier method and analyzed by the logrank test were statistically different for distant metastases-free survival (P = 0.03) and for overall survival (P = 0.01). The relative risk in patients with post-QUART local recurrence for distant metastases was 2.09 and for death 2.34. Conclusions It was concluded that post-QUART local recurrences are a poor prognostic factor in patients with early infiltrating breast carcinoma.

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E7389, a novel anti-tubulin, in patients with refractory breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.653 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 653-653 ◽

Cited By ~ 5

Author(s):

J. BlumL. Forero ◽

M. K. Heiskala ◽

N. Meneses ◽

K. Chandrawansa ◽

F. Fang ◽

...

Keyword(s):

Breast Cancer ◽

Performance Status ◽

Safety Data ◽

Synthetic Analog ◽

Open Label ◽

Ecog Performance Status ◽

Group 2 ◽

Grade 3 ◽

Cycle Group ◽

Group 1

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]

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Final Results of ECOG1100: A phase I/II study of combined blockade of the ErbB receptor network in patients with HER2- overexpressing metastatic breast cancer (MBC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.1033 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 1033-1033 ◽

Cited By ~ 2

Author(s):

S. L. Moulder ◽

A. O’Neill ◽

C. Arteaga ◽

M. Pins ◽

J. Sparano ◽

...

Keyword(s):

Breast Cancer ◽

Phase I ◽

Cell Lines ◽

Dose Level ◽

Phase Ii ◽

Prior Exposure ◽

Prior Chemotherapy ◽

Group 2 ◽

Grade 3 ◽

Group 1

1033 Background: Activation of EGF receptor has been associated with resistance to trastuzumab in breast cancer cell lines. EGFR tyrosine kinase inhibitors inhibit HER2 phosphorylation and synergize with trastuzumab in HER2+ cell lines that co-express EGFR. Methods: Pts with MBC and HER2 overexpression by immunohistochemistry (3+) and/or HER2 gene-amplification by FISH, 0–2 prior chemotherapy regimens for met disease, LVEF 50%, and no prior trastuzumab were treated with trastuzumab 2 mg/kg/wk and gefitinib 250- 500 mg/day until disease progression, unacceptable toxicity or withdrawal of consent. The phase I portion of the trial used a 3+3 design to determine MTD. In the phase II portion of the trial, patients were stratified based upon prior chemotherapy exposure (Group 1= no prior exposure to chemotherapy, Group 2= prior exposure to 1–2 chemotherapy regimens). Response measured using RECIST criteria. The primary endpoint was to increase proportion progression free from 50 to 65% at 6 months in Group 1 and from 50 to 70% at 3 months in Group 2. Results: Phase I: DLT (Grade 3 diarrhea) occurred in 2/3 patients treated at the 500 mg/day dose level of gefitinib in combination with weekly trastuzumab. 0/3 patients treated at the 250 mg/day dose level experienced DLT. This was considered MTD and was the dose selected for the Phase II portion of the trial. Phase II: 36 eligible pts were enrolled. Most patients were ECOG PS of 0 and had visceral organ involvement. Of the patients enrolled in Group 1, one pt achieved a CR, one PR and 7 had SD (≥ 24 weeks). Median time to progression (TTP) was 2.9 months (95% CI, 2.5–4). In Group 2 no responses were observed with a median TTP of 2.5 months (95% CI, 1.5- 2.7). Most common severe toxicities were rash (grade 3, 14%) and diarrhea (grade 3, 30%). No grade 3 cardiac toxicity was encountered. Conclusions: Trastuzumab in combination with gefitinib at doses of 250 mg/day demonstrated an acceptable toxicity profile; however, during planned interim analysis, the TTP did not meet predetermined statistical endpoints required for study continuation. These results do not support the further use of this combination and have implications for other trials using trastuzumab and EGFR TK inhibitors simultaneously. [Table: see text]

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Lymphocyte Subpopulations in Patients with Advanced Breast Cancer Submitted to Neoadjuvant Chemotherapy

Tumori Journal ◽

10.1177/030089160008600507 ◽

2000 ◽

Vol 86 (5) ◽

pp. 403-407 ◽

Cited By ~ 28

Author(s):

Eddie Fernando Candido Murta ◽

Jurandyr Moreira de Andrade ◽

Roberto Passeto Falcio ◽

Sérgio Bighetti

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Advanced Breast Cancer ◽

B Lymphocytes ◽

Interleukin 2 ◽

Advanced Breast ◽

Control Group ◽

Percentage Increase ◽

Group 2 ◽

Group 1

Aims and background There is an enhanced immune response in patients with breast cancer after the use of chemotherapy. The objective of this study was therefore to investigate alterations in the number of peripheral lymphocytes in patients with breast cancer after neoadjuvant chemotherapy (NC) and the relationship with prognosis. Methods Thirty women were analyzed. Their UICC staging was IIb (only T3N0 included) and III (N3 not included). Sample analysis was performed using flow cytometry before the first cycle and 18 to 21 days after the last cycle of NC. The lymphocyte subsets studied were: T (CD3, CD4, CD8), B (CD19, CD23), natural killer (NK) (CD56, CD16), and interleukin-2 (CD25). CD3, CD56, CD8, and CD16 lymphocytes were analyzed with double marking. After x = 3.8 ± 1.3 cycles of 5-fluorouracil, epirubicin and cyclophosphamide (FEC), 16 patients showed a complete or partial response (group 1). After three cycles 14 showed no response or tumor progression (group 2). A control group of healthy women was used for pretreatment analysis. Results Before NC there was a significant increase in B lymphocytes and NK cells in comparison to the control group. After NC there was a significant percentage increase in CD3, CD4, CD8, CD25 and CD3+CD56+ cells and a decrease in CD19, CD23, CD56, CD16 and CD16+CD8+ cells. There was a significant fall in the absolute number of CD4, CD19, CD23, CD56, CD16 and CD16+CD8+ lymphocytes and an increase in GD3+CD56+ lymphocytes. Before NC the ratio CD4/CD8 in group 1 was 2.25 ± 0.5 and in group 2 it was 1.79 ± 0.5 (P <0.05). Conclusions Patients with advanced breast cancer showed increases in B and NK lymphocytes. Neoadjuvant chemotherapy (FEC) caused an increase in CD3+CD56+ and a decrease in B lymphocytes. Patients with an increased CD4/CD8 ratio have a better chance of responding to neoadjuvant chemotherapy.

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Expression level of serum circulating miRNA-21, miRNA-10b and miRNA-200c in breast cancer patients with sentinel lymph node metastasis*

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0013.2562 ◽

2019 ◽

Vol 73 ◽

pp. 325-332

Author(s):

Sebastian Niedźwiecki ◽

Janusz Piekarski ◽

Bożena Szymańska ◽

Zofia Pawłowska ◽

Arkadiusz Jeziorski

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Sentinel Lymph Node ◽

Lymph Node Metastasis ◽

Cancer Patients ◽

Sentinel Lymph Node Metastasis ◽

Breast Cancer Patients ◽

Node Metastasis ◽

Group 2 ◽

Group 1

MicroRNAs (miRNAs) act a role in regulation numerous processes crucial for oncogenesis. The aim of the study was to compare the blood serum concentrations of selected microRNAs (miRNA-21, miRNA-10b and miRNA-200c) between breast cancer patients without sentinel lymph node metastasis (Group 1) and those with metastasis (Group 2). The serum levels of miRNA-21, miRNA-10b and miRNA-200c were measured with using TaqMan PCR assays performed on a 7900HT Fast Real-Time PCR System in two groups of breast cancer patients: Group 1 – without sentinel lymph node metastasis (32 patients) and Group 2 – with sentinel lymph node metastasis (14 patients). The mean level of miRNA-200c was noticeably lower in Group 2 than in Group 1. The mean fold change of miRNA-200c level in the metastatic group (Group 2) was approximately 1.3 times lower than that in non-metastatic group (Group 1). However, this result just approached the arbitrary threshold for significance (p = 0.05). Breast cancer patients with sentinel lymph node metastasis demonstrate diminished levels of circulating miR-200c compared to non-metastatic patients.

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Vliyanie sulodeksida na funktsional'noe sostoyanie endoteliya u bol'nykh s sakharnym diabetom i diabeticheskoyretinopatiey

Diabetes Mellitus ◽

10.14341/2072-0351-5637 ◽

2011 ◽

Vol 14 (2) ◽

pp. 66-68

Author(s):

Natalya Alexandrovna Gavrilova ◽

Olga Evgen'evna Tishchenko

Keyword(s):

Nitric Oxide ◽

Endothelial Function ◽

Functional State ◽

Vascular Wall ◽

Vasoactive Factors ◽

Endothelial Factors ◽

Group 2 ◽

Willebrand Factor ◽

Stimulation Of ◽

Group 1

Aim. To study effect of sulodexide (Vessel Due F) on the functional state of endothelium in patients with diabetic retinopathy. Materials and methods. A total of 37 patients with DR were divided in 2 groups and treated with sulodexide. Group 1 comprised 16 patients withnon-proliferative DR, group 2 included 21 patients with preproliferative DR. The functional state of endothelium was estimated from the plasma andserum levels of endothelial factors (sVCAM, endothelin, nitric oxide, t-PA, Willebrand factor). Results. The measurement of the initial levels of endothelial factors in both groups revealed significant changes in endothelin, nitric oxide, and sVCAMsuggesting disturbances of endothelial function due to DR. Sulodexide therapy normalized it regardless of DR stage and thereby improved functionalactivity of retina. Conclusion. This study has demonstrated beneficial effect of sulodexide on endothelial function in patients with DR due to correction of the productionof vasoactive factors (endothelin, nitric oxide) and stimulation of fibrinolytic activity of the vascular wall (t-PA).

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Roles of neutrophil/lymphocyte ratio in prognosis and in differentiation of potential beneficiaries in HER2-positive breast cancer with trastuzumab therapy

10.21203/rs.2.19005/v1 ◽

2019 ◽

Author(s):

Nianhua Ding ◽

Juan Huang ◽

Ningsha Li ◽

Jiaqi Yuan ◽

Shouman Wang ◽

...

Keyword(s):

Breast Cancer ◽

Her2 Positive ◽

Neutrophil Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Trastuzumab Treatment ◽

Her2 Positive Breast Cancer ◽

Group 3 ◽

Group 2 ◽

Group 1 ◽

Positive Breast Cancer

Abstract Purpose: The relationship of neutrophil/lymphocyte ratio (NLR) with prognosis of HER2-positive breast cancer (BC) are not well studied. We aimed to assess the prognostic role of NLR in HER2-positive BC patients treated with or without trastuzumab.Methods: The clinical data of 843 HER2-positive BC patients from July 2013 to July 2018 were collected. The difference among variables was calculated by chi-square test. The associations between clinicopathological factors, NLR and disease-free survival (DFS) were analyzed by univariate and multivariate analyses.Results : Patients were divided into three groups. In group 1 containing 255 patients without trastuzumab treatment, pretreatment NLR showed no predictive value. Patients with trastuzumab treatment were divided into two groups on equal, according to pretreatment NLR values, low NLR (group 2) and high NLR (group 3). Patients in group 2 showed significantly higher 3-year DFS rate than patients in group 1 and group 3 (95.3% vs. 91.6% vs. 90.5%, respectively, P = 0.011); patients in the group 1 and group 3 had similar 3-year DFS outcome. Multivariate analysis showed high pretreatment NLR was significantly associated with shorter DFS (HR = 2.917, 95% CI=1.055-8.062, P = 0.039) in HER2-positive BC patients treated with trastuzumab. Conclusion : Among HER2-positive trastuzumab-treated BC patients, low pretreatment NLR value was associated with better DFS, and it might help to differentiate potential beneficiaries of trastuzumab treatment.

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