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- Hessmann, E, et al.
(författare)
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Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer
- 2018
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 67:3, s. 497-507
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Tidskriftsartikel (refereegranskat)abstract
- Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery.DesignGemcitabine metabolites were analysed in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation.ResultsGemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2′,2′-difluorodeoxycytidine-5′-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2′,2′-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5′-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%.ConclusionsOur findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.
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- Rurik, I., et al.
(författare)
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Early and Menopausal Weight Gain and its Relationship with the Development of Diabetes and Hypertension
- 2017
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Ingår i: Experimental and Clinical Endocrinology & Diabetes. - : Georg Thieme Verlag KG. - 0947-7349 .- 1439-3646. ; 125:04, s. 241-250
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous research has revealed a clear relationship between weight gain of persons and their metabolic diseases developing later. These studies have covered only short periods lasting 4–8 years. Our goal was to collect decades’ old and often life-long anthropometric data and correlate the figures with the presence of hypertension and diabetes or both. Methods: A retrospective international study was planned and organized to compare self-recorded data of lifelong weight gain among 60–70-year-old patients, analyze their correlation with metabolic diseases they developed, with special attention to women’s weight gain around pregnancy, delivery and menopause in primary care settings in Germany, Hungary, Italy, Slovakia and the Ukraine. Results: Of the recruited 815 participants, 319 men and 496 women presented all the required data. Diabetics of both genders had the highest baseline weight at 20 years of age. The weight and BMI of the whole study population increased steadily until their seventies, but to a lesser extent after their fifties. Compared to the control group, changes over decades were the greatest among diabetics and also greater among patients with hypertension. Weight increase in the first decades (20–30-year-old men and 30–40-year-old women) was a significant risk factor for the development of diabetes (OR=1.044; p=0.002; 95% CI: 1.01–1.07). Among patients with diabetes and hypertension, both diagnoses were set up earlier than among those with a single morbidity. Among females, weight increase around pregnancy and menopause correlated significantly with higher odds for the diagnoses of diabetes and/or hypertension, irrespective of the number of children. Conclusions: During their decade-long relationship with their patients, family physicians are expected to identify the higher weight gain of their patients, especially among younger generation and intervene, if necessary.
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