A tüszőfolyadék biomarkereinek vizsgálata in vitro fertilizációs kezelésben részesült betegekben

Összefoglaló. A szerzők ismertetik vizsgálataik eredményeit, melyeket a közelmúltban az in vitro fertilizációs kezelésben részesülő betegeikben a tüszőfolyadék biomarkereinek analízisével értek el. A vizsgálatok célja annak feltárása volt, hogy az in vitro fertilizációs eljárás során a petesejtek aspirációjakor nyert tüszőfolyadék-biomarkerek lokális/ovarialis vagy szisztémás eredetűek, és milyen összefüggést mutatnak az in vitro fertilizáció eredményességét jelző paraméterekkel. Megerősítettük, hogy az autokrin/parakrin szerotoninrendszer már a fejlődés legkorábbi időszakában is működőképes, és mind az anyai szérum, mind a tüszőfolyadék szerotoninszintje szignifikáns pozitív összefüggést mutatott az érett petesejtek számával és a klinikai terhességgel (β = 0,447, p = 0,015, illetve β = 0,443, p = 0,016). Az agyi eredetű neurotrofikus faktor (BDNF) esetében ilyen kapcsolat nem volt igazolható, de a tüszőfolyadék BDNF- és szerotoninszintjei közötti pozitív korreláció (r = 0,377, p = 0,040) azt mutatja, hogy a két neurohormon 'feed-forward' (előrecsatoló ) szabályozása ovarialis szinten is működik. A hypothalamicus kisspeptin esetében csupán a posztstimulációs anyai szérumhormonszint befolyásolta az érett petesejtek számát (β = 0,398, p = 0,029). A triptofán-kinurenin-szerotonin rendszer elemzése azt mutatta, hogy kedvezőbb in vitro fertilizációs kimenetel várható, ha a szerotonin-kinurenin egyensúly a szerotonin javára tolódik el. Az oxidatívstressz-markerek közül vizsgálták a DNS-károsodás biomarkerét, a 8-hidroxi-2'-deoxiguanozin és a totális antioxidáns-kapacitás szérum- és tüszőfolyadékszintjeit, és megállapították, hogy mindkét marker kedvezőtlenül befolyásolja az életképes embriók számát (r = 0,302, p = 0,027 és r = 0,268, p = 0,039). A protektív hatású szirtuinok - nikotinamid-adenin-dinukleotid-függő hiszton-deacetiláz fehérjék - közül a vizsgált szirtuin-1 és szirtuin-6 a szérumszintektől függetlenül kimutatható a tüszőfolyadékban. Szignifikáns pozitív korreláció van a tüszőfolyadék-szirtuin-6 és az érettpetesejt-szám (F = 6,609, p = 0,016), valamint a szérum-szirtuin-1 (F = 10,008, p = 0,005) és a szérum-szirtuin-6 (F = 5,268, p = 0,031) és a klinikai terhesség gyakorisága között. Eredményeink alapján megállapítható, hogy a tüszőfolyadék biomarkereinek vizsgálata javíthatja az in vitro fertilizáció kimenetelének megítélését. Orv Hetil. 2021; 162(14): 523-529. Summary. This article outlines the result of recent studies on several follicular fluid biomarkers in patients undergoing in vitro fertilization. The aim of these studies was to investigate whether 1) the follicular fluid biomarkers in question are produced locally by the ovaries or they originate from the circulating plasma, 2) and to establish their association with parameters of in vitro fertilization outcome. It was confirmed that the autocrine/paracrine serotonin system is functional already at the earliest stage of development and both maternal serum and follicular fluid serotonin levels were positively related to the number of mature oocytes (β = 0.447, p = 0.015 and β = 0.443, p = 0.016, respectively) and clinical pregnancy (β = 1.028, p = 0.047). Such associations for brain-derived neurotrophic factor (BDNF) could not be found, but BDNF and serotonin in the follicular fluid were closely related (r = 0.377, p<0.040) suggesting that the feed-forward regulation of these neurohormones is activated at ovarian level. The hypothalamic kisspeptin in the post-stimulation maternal serum also increased the number of mature oocytes (β = 0.398, p = 0.029). Analysis of the tryptophan-kynurenine-serotonin system showed a more favourable in vitro fertilization outcome when the serotonin-kynurenine balance was shifted and serotonin predominated over kynurenine. The oxidative stress markers, 8-hydroxy-2'-deoxyguanosine, an indicator of DNA damage and the total antioxidant capacity in follicular fluid and maternal serum had negative impact on the number of viable embryos (r = 0.302, p = 0.027 and r = 0.268, p = 0.039), respectively. The protective sirtuins - the nicotinamide adenine dinucleotide-dependent histone deacetylase proteins - could be detected in follicular fluid irrespective of their maternal serum levels. Significant positive relationship was demonstrated between follicular fluid sirtuin 6 and mature oocytes (F = 6.609, p = 0.016) as well as between serum sirtuin 1 (F = 10.008, p = 0.005) and serum sirtuin 6 (F = 5.268, p = 0.031) and the rate of clinical pregnancy, respectively. On the basis of these results, it can be concluded that measuring several follicular fluid biomarkers may improve the prediction of the outcome of in vitro fertilization. Orv Hetil. 2021; 162(14): 523-529

Luteinizing hormone–releasing hormone (LH–RH) antagonist Cetrorelix inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of IGF-II in tumors

In previous studies, we showed that LH–RH antagonist Cetrorelix inhibits the growth of DU-145 and PC-3 human androgen-independent prostate cancers in nude mice. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer with Cetrorelix at a dose of 100 μg/animal subcutaneously (s.c.) once a day. Tumor growth, serum and tumor levels of IGF-I and -II as well as the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of treatment, final volume and weight of DU-145 tumors in mice treated with Cetrorelix were significantly decreased compared with controls and serum IGF-1 showed a significant reduction. Therapy with Cetrorelix also reduced by 84% the levels of IGF-II in DU-145 tumor tissue compared with controls, but did not affect the concentration of IGF-I. RT–PCR analyses revealed a high expression of mRNA for IGF-II, but not for IGF-I in DU-145 tumors. Treatment with Cetrorelix decreased the expression of IGF-II mRNA by 78% ( p<0.01) as compared with controls. Our study indicates that LH–RH antagonist Cetrorelix may inhibit the growth of DU-145 human androgen-independent prostate cancers by decreasing the production and mRNA expression of IGF-II by the tumor tissue. This also suggests that LH-RH antagonist Cetrorelix could interfere with the signal transduction pathways involving IGF-II, leading to tumor growth inhibition

Growth hormone-releasing hormone antagonist MZ-5-156 inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of insulin-like growth factor II in tumors

Insulin-like growth factors I and II (IGF-I and -II) are potent mitogens for various cancers, including carcinoma of the prostate. In several experimental cancers, treatment with antagonists of growth hormone-releasing hormone (GH-RH) produces a reduction in IGF-I and -II, concomitant to inhibition of tumor growth. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer for 8 weeks with potent GH-RH antagonist MZ-5-156 at a dose of 20 μg/animal s.c. twice a day. Tumor growth, serum and tumor levels of IGF-I and -II, and the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of therapy, final volume and weight of DU-145 tumors in mice treated with MZ-5-156 were significantly (P < 0.01) decreased compared with controls, and serum IGF-I showed a significant reduction. Treatment of nude mice bearing DU-145 xenografts with MZ-5-156 also significantly (P < 0.01) diminished by 77% the levels of IGF-II in tumor tissue compared with controls, but did not affect the concentration of IGF-I. Reverse transcription–PCR analyses revealed a high expression of IGF-II mRNA in DU-145 tumors. Treatment with GH-RH antagonist MZ-5-156 decreased the expression of IGF-II mRNA by 58% (P < 0.01) as compared with controls. Our work suggests that GH-RH antagonist MZ-5-156 may inhibit the growth of DU-145 human androgen-independent prostate cancers through a reduction in the production and mRNA expression of IGF-II by the tumor tissue. These findings extend our observations on the mechanism of action of GH-RH antagonists and may explain how GH-RH antagonists inhibit tumor growth

Bombesin/gastrin‐releasing peptide antagonists RC‐3095 and RC‐3940‐II inhibit tumor growth and decrease the levels and mRNA expression of epidermal growth factor receptors in H‐69 small cell lung carcinoma

BACKGROUND Antagonists of bombesin/gastrin‐releasing peptide (BN/GRP) have been developed to block the autocrine stimulatory effect of BN/GRP on tumors such as small cell lung carcinoma (SCLC). Although several studies have addressed the intracellular events that follow the formation of the receptor‐ligand complex, the mechanism of action of BN/GRP antagonists remains unclear. METHODS In this study the authors investigated the effect of synthetic BN/GRP antagonists RC‐3095 and RC‐3940‐II on tumor growth and the expression of epidermal growth factor receptors (EGF‐R) in H‐69 SCLC. Athymic nude mice xenografted with H‐69 SCLC were treated subcutaneously for 5 weeks with RC‐3095 and RC‐3940‐II at the dose of 10 μg/animal/day. RESULTS RC‐3095 decreased tumor volume by approximately 50% (P < 0.05) and RC‐3940‐II by 70‐60% (P < 0.01). Tumor burden also was significantly decreased in the groups treated with RC‐3095 and RC‐3940‐II. Receptor analyses demonstrated high affinity binding sites for BN/GRP and EGF on the untreated H‐69 SCLC tumors. After treatment with RC‐3095 and RC‐3940‐II, the concentration of receptors for BN/GRP was decreased by 29.0% and 36.5%, respectively (both, P < 0.01) compared with controls, and EGF‐R levels were reduced by 62.3% and 63.0%, respectively (both, P < 0.01). Reverse transcriptase‐polymerase chain reaction and Southern blot analyses revealed that the levels of mRNA for EGF‐R in tumors were lowered by 31% (P < 0.05) and 43% (P < 0.01), respectively, after treatment with RC‐3095 and RC‐3940‐II. CONCLUSIONS This study indicates that the inhibition of growth of H‐69 SCLC by BN/GRP antagonists RC‐3095 and RC‐3940‐II is accompanied by a marked decrease in the levels and mRNA expression of EGF‐R. Cancer 1998;83:1335‐1343. © 1998 American Cancer Society. Bombesin antagonists RC‐3095 and RC‐3940‐II effectively inhibited growth of H‐69 small cell lung carcinoma in nude mice and reduced the level and mRNA expression of epidermal growth factor receptors on tumor membranes. These peptide analogs should be considered for the treatment of small cell lung carcinoma

A monochorialis ikerterhességekben előforduló kórképek és a monochorialis ikerterhességek gondozása

Nem ismer

Targeted cytotoxic analogue of somatostatin AN-238 inhibits growth of androgen-independent Dunning R-3327-AT-1 prostate cancer in rats at nontoxic doses

L