Mélyen infiltráló colorectalis endometriosis miatt végzett multidiszciplináris laparoszkópos műtétek során szerzett tapasztalataink

Introduction: Deep infiltrating endometriosis is a particular form of endometriosis that penetrates the peritoneal surface or it reaches the subserosal neurovascular plexus. Aim: The aim of the authors was to analyze the results of segmental colorectal resections performed for deep infiltrating endometriosis. Method: Between 2009 and 2012, 50 patients underwent segmental rectum or/and sigmoid resection for endometriosis. Results: 21 patients had ultralow rectal resection and 29 patients had low colorectal anastomosis or anterior resection. Concomitant intervention in other organs was required in all cases, including gynecologic procedures (n = 50), additional gynecologic (n = 47), vesical (n = 9) and ureteral (n = 18) resections. The mean number of endometriosis lesions was 2.4+/-1.8 per patient. In all patients fertility was preserved. Severe surgical complications (Clavien-Dindo stage III or more severe) occurred in 3 patients (6%). Conclusions: The results confirm that segmental bowel resection is an efficient and safe method for the treatment of deep infiltrating colorectal endometriosis. Orv. Hetil., 2014, 155(5), 182-186

A leggyakoribb nem onkológiai eredetű nőgyógyászati kórképek epigenetikai háttere

Epigenetic effects influence the function of genes regulating the main physiological mechanisms. Some of these environmental factors may reduce or inhibit the function of these genes. The environmental effects on gene function may result in a change of the DNA structure leading to non-heritable phenotype changes. Epigenetic factors play an important etiological role in the development of numerous diseases in obstetrics and gynecology. Uterine fibroids probably have a complex etiological background including epigenetic mechanisms. The multifactorial aetiology of endometriosis suggests key roles for immunological and hormonal factors in the development of the diseases. These mechanisms are influenced by epigenetic factors, which may serve as therapeutic targets in the future. The possible in utero origin of polycystic ovary syndrome determines the main directions of research concerning epigenetic factors in the etiological background, with the hope of eventual prevention and/or treatment in the preconceptional period as well as during pregnancy care. Orv. Hetil., 2014, 155(13), 492-499

Selective antiproliferative effect of C-2 halogenated 13α-estrones on cells expressing Organic anion-transporting polypeptide 2B1 (OATP2B1)

Organic anion-transporting polypeptide 2B1 (OATP2B1) is a multispecific transporter mediating the cellular uptake of steroids and numerous drugs. OATP2B1 is abundantly expressed in the intestine and is also present in various tumors. Increased steroid hormone uptake by OATP2B1 has been suggested to promote progression of hormone dependent tumors. 13 alpha-estrones are effective inhibitors of endogenous estrogen formation and are potential candidates to inhibit proliferation of hormone dependent cancers. Recently, we have identified a variety of 13 alpha/beta-estrone-based inhibitors of OATP2B1. However, the nature of this interaction, whether these inhibitors are potential transported substrates of OATP2B1 and hence may be enriched in OATP2B1overexpressing cells, has not yet been investigated. In the current study we explored the antiproliferative effect of the most effective OATP2B1 inhibitor 13 alpha/beta-estrones in control and OATP2B1-overexpressing A431 carcinoma cells. We found an increased antiproliferative effect of 3-O-benzyl 13 alpha/beta-estrones in both mock transfected and OATP2B1-overexpressing cells. However, C-2 halogenated 13 alpha-estrones had a selective OATP2B1-mediated cell growth inhibitory effect. In order to demonstrate that increased sensitization can be attributed to OATP2B1-mediated cellular uptake, tritium labeled 2-bromo-13 alpha-estrone was synthesized for direct transport measurements. These experiments revealed increased accumulation of [H-3]2-bromo-13 alpha-estrone due to OATP2B1 function. Our results indicate that C-2 halogenated 13 alpha-estrones are good candidates in the design of anti-cancer drugs targeting OATP2B1

Structural dissection of 13-epiestrones based on the interaction with human Organic anion-transporting polypeptide, OATP2B1

Human OATP2B1 encoded by the SLCO2B1 gene is a multispecific transporter mediating the cellular uptake of large, organic molecules, including hormones, prostaglandins and bile acids. OATP2B1 is ubiquitously expressed in the human body, with highest expression levels in pharmacologically relevant barriers, like enterocytes, hepatocytes and endothelial cells of the blood-brain-barrier. In addition to its endogenous substrates, OATP2B1 also recognizes clinically applied drugs, such as statins, antivirals, antihistamines and chemotherapeutic agents and influences their pharmacokinetics. On the other hand, OATP2B1 is also overexpressed in various tumors. Considering that elevated hormone uptake by OATP2B1 results in increased cell proliferation of hormone dependent tumors (e.g. breast or prostate), inhibition of OATP2B1 can be a good strategy to inhibit the growth of these tumors. 13-epiestrones represent a potential novel strategy in the treatment of hormone dependent cancers by the suppression of local estrogen production due to the inhibition of the key enzyme of estrone metabolism, 17ß-hydroxysteroid-dehydrogenase type 1 (HSD17ß1). Recently, we have demonstrated that various phosphonated 13-epiestrones are dual inhibitors also suppressing OATP2B1 function. In order to gain better insights into the molecular determinants of OATP2B1 13-epiestrone interaction we investigated the effect of C-2 and C-4 halogen or phenylalkynyl modified epiestrones on OATP2B1 transport function. Potent inhibitors (with EC50 values in the low micromolar range) as well as non-inhibitors of OATP2B1 function were identified. Based on the structure-activity relationship (SAR) of the various 13-epiestrone derivatives we could define structural elements important for OATP2B1 inhibition. Our results may help to understand the drug/inhibitor interaction profile of OATP2B1, and also may be a useful strategy to block steroid hormone entry into tumors

Synthesis and in vitro photodynamic activity of aza-BODIPY-based photosensitizers

Aza-BODIPY dyes have recently come to attention owing to their excellent chemical and photophysical properties. In particular, their absorption and emission maxima can efficiently be shifted to the red or even to the NIR spectral region. On this basis, aza-BODIPY derivatives are widely investigated as fluorescent probes or phototherapeutic agents. Here we report the synthesis of a set of novel aza-BODIPY derivatives as potential photosensitizers for use in photodynamic therapy. Triazolyl derivatives were obtained via Cu(I)-catalyzed azide-alkyne cycloaddition as the key step. In vitro photodynamic activities of the newly synthesized compounds were evaluated on the A431 human epidermoid carcinoma cell line. Structural differences influenced the light-induced toxicity of the test compounds markedly. Compared to the initial tetraphenyl aza-BODIPY derivative, the compound bearing two hydrophilic triethylene glycol side chains showed substantial, more than 250-fold, photodynamic activity with no dark toxicity. Our newly synthesized aza-BODIPY derivative, acting in the nanomolar range, might serve as a promising candidate for the design of more active and selective photosensitizers

Structural dissection of 13-epiestrones based on the interaction with human Organic anion-transporting polypeptide, OATP2B1

Human OATP2B1 encoded by the SLCO2B1 gene is a multispecific transporter mediating the cellular uptake of large, organic molecules, including hormones, prostaglandins and bile acids. OATP2B1 is ubiquitously expressed in the human body, with highest expression levels in pharmacologically relevant barriers, like enterocytes, hepatocytes and endothelial cells of the blood-brain-barrier. In addition to its endogenous substrates, OATP2B1 also recognizes clinically applied drugs, such as statins, antivirals, antihistamines and chemotherapeutic agents and influences their pharmacokinetics. On the other hand, OATP2B1 is also overexpressed in various tumors. Considering that elevated hormone uptake by OATP2B1 results in increased cell proliferation of hormone dependent tumors (e.g. breast or prostate), inhibition of OATP2B1 can be a good strategy to inhibit the growth of these tumors. 13-epiestrones represent a potential novel strategy in the treatment of hormone dependent cancers by the suppression of local estrogen production due to the inhibition of the key enzyme of estrone metabolism, 17ß-hydroxysteroid-dehydrogenase type 1 (HSD17ß1). Recently, we have demonstrated that various phosphonated 13-epiestrones are dual inhibitors also suppressing OATP2B1 function. In order to gain better insights into the molecular determinants of OATP2B1 13-epiestrone interaction we investigated the effect of C-2 and C-4 halogen or phenylalkynyl modified epiestrones on OATP2B1 transport function. Potent inhibitors (with EC50 values in the low micromolar range) as well as non-inhibitors of OATP2B1 function were identified. Based on the structure-activity relationship (SAR) of the various 13-epiestrone derivatives we could define structural elements important for OATP2B1 inhibition. Our results may help to understand the drug/inhibitor interaction profile of OATP2B1, and also may be a useful strategy to block steroid hormone entry into tumors

New way to green biological assays fluorescent steroids replace radioisotopes

Novel BODIPY–estrone and BODIPY–estradiol conjugates have been synthesized via Cu(I)- catalyzed azide-alkyne click (CuAAC) and/or Sonogashira reactions by selecting position C3-O for labeling. The steroidal azides and/or bromides were reacted with BODIPY-based fluorescent dye bearing alkyne function. The new fluorescent estrone conjugates might replace radiolabeled compounds in certain biochemical assays

Az idegkímélő műtéti technika jelentősége a mélyen infiltráló endometriosis sebészetében

Absztrakt Bevezetés: A mélyen infiltráló endometriosis kezelésében az elváltozások hagyományos sebészi eltávolítása súlyos szövődményekkel járhat. Célkitűzés: Idegkímélő, illetve hagyományos technikával végzett műtétek összehasonlítása, az egyes szövődmények előfordulási gyakoriságának ismertetése mélyen infiltráló endometriosissal foglalkozó munkacsoportok műtéti eredményeinek összefoglalásával. Módszer: A szerzők retrospektív elemzést végeztek a 2004. március 31. és 2015. március 31. között megjelent tudományos közlemények felhasználásával. A keresést a http://www.pubmed.org adatbázisban végezték az „endometriosis”, „deep infiltrating,” „nerve-sparing, surgery” (endometriosis, mélyen infiltráló, idegkímélő, sebészet) keresőszavak kombinációjának alkalmazásával. Eredmények: Mélyen infiltráló endometriosis kapcsán végzett, nem idegkímélő beavatkozásokat követően 19,1–38,5%-ban jelentkezhet átmeneti húgyhólyag-diszfunkció, míg idegkímélő műtéti technika alkalmazását követően a betegek 0,61–33,3%-ában fordulhat elő. Nem idegkímélő technika alkalmazását követően a betegek átlagosan 121,1 napig, idegkímélő műtéteket követően 7–39,8 napig szorultak önkatéterezésre. Krónikus húgyhólyag-diszfunkció mélyen infiltráló endometriosis miatt végzett idegkímélő műtéteket követően nem fordult elő. Következtetések: Az idegkímélő technikák alkalmazása a betegek életminőségének jelentős javulását eredményezi, mivel panaszaik kezelése mellett alacsonyabb posztoperatív szövődményrátával társul. Orv. Hetil., 2015, 156(48), 1960–1965

Az idegkímélő műtéti technika jelentősége a mélyen infiltráló endometriosis sebészetében

INTRODUCTION: Traditional surgeries performed in cases of deep infiltrating endometriosis lead to impaired quality of life. AIM: To summarize the postoperative outcome and to compare the rate of postoperative complications after different therapeutic approaches applied in deep infiltrating endometriosis. METHOD: The authors analized the articles published between March 31, 2004 and March 31, 2015, in the database http://www.pubmed.org using the following keywords: endometriosis, deep infiltrating, nerve sparing, surgery. RESULTS: Non-nerve sparing surgery resulted in temporary urinary dysfunction in 19.1-38.5% of patients, while it occurred in 0.61-33.3% of patients after nerve-sparing surgery. Non-nerve sparing surgical technique resulted in an avarage of 121 days of need for self-catheretisation. When nerve-sparing surgeries were performed the duration of self-catheterisation varied between 7 to 39.8 days. After nerve sparing surgeries, permanent bladder dysfunction was not detected in any case. CONCLUSIONS: Because of the successful treatment of the patients symptoms and the lower postoperative complication rate, nerve-sparing surgical technique leads to a significant improvement of the quality of life. Orv. Hetil., 2015, 156(48), 1960-1965