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1.
Anticancer Res ; 42(4): 1821-1832, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35347000

ABSTRACT

BACKGROUND/AIM: Satraplatin is an oral platinum analog with proven clinical efficacy and a more favorable toxicity profile, although with increased hematotoxicity, when compared to cisplatin. Hence, we carried out a systematic biomarker analysis to identify hematological malignancies with high susceptibility to satraplatin. MATERIALS AND METHODS: Half-maximal inhibitory concentrations (IC50) for satraplatin and cisplatin were determined for 66 different cancer cell lines by CTG Luminescent Cell Viability Assay. In a second step, whole transcriptome RNA sequencing and whole-exome DNA sequencing technology followed by unbiased analysis of gene expression, gene mutation and copy number levels were performed and correlated with drug efficacy. RESULTS: Satraplatin was significantly more active against hematological malignancies compared to solid organ cancer. In addition, satraplatin showed a significantly more potent antiproliferative activity compared to cisplatin in most lymphoma cell lines achieving sub micromolar IC50 values. Single BCL2 apoptosis regulator (BCL2) gene mutation and 9p21 copy-number deletions including S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency were identified as key characteristics for high sensitivity to satraplatin. CONCLUSION: Satraplatin demonstrated a high cytotoxic activity in genetically well-defined hematological malignancies which is distinct from that of cisplatin. MTAP deficiency was identified as biomarker of enhanced satraplatin efficacy in hematological cancer-derived cell lines. These data in combination with the lipophilicity of satraplatin provide the rationale for targeting specific lymphatic entities such as primary central nervous system lymphoma and cutaneous T-cell lymphoma to improve clinical outcome.


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Humans , Neoplasms/drug therapy , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use
2.
Cancer Res ; 68(13): 5152-8, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18593914

ABSTRACT

Serotonin, a neurotransmitter with numerous functions in the central nervous system (CNS), is emerging as an important signaling molecule in biological processes outside of the CNS. Recent advances have implicated serotonin as a regulator of inflammation, proliferation, regeneration, and repair. The role of serotonin in tumor biology in vivo has not been elucidated. Using a genetic model of serotonin deficiency (Tph1(-/-)) in mice, we show serotonin to be crucial for the growth of s.c. colon cancer allografts in vivo. Serotonin does not enhance tumor cell proliferation but acts as a regulator of angiogenesis by reducing the expression of matrix metalloproteinase 12 (MMP-12) in tumor-infiltrating macrophages, entailing lower levels of angiostatin-an endogenous inhibitor of angiogenesis. Accordingly, serotonin deficiency causes slower growth of s.c. tumors by reducing vascularity, thus increasing hypoxia and spontaneous necrosis. The biological relevance of these effects is underscored by the reconstitution of serotonin synthesis in Tph1(-/-) mice, which restores allograft phenotype in all aspects. In conclusion, we show how serotonin regulates angiogenesis in s.c. colon cancer allografts by influencing MMP-12 expression in tumor-infiltrating macrophages, thereby affecting the production of circulating angiostatin.


Subject(s)
Colonic Neoplasms/blood supply , Macrophages, Peritoneal/physiology , Neovascularization, Pathologic/etiology , Serotonin/physiology , Angiostatins/metabolism , Animals , Carcinoma, Lewis Lung/blood supply , Carcinoma, Lewis Lung/genetics , Cell Proliferation , Colonic Neoplasms/pathology , Disease Models, Animal , Macrophages, Peritoneal/drug effects , Matrix Metalloproteinase 12/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasm Transplantation , Serotonin/deficiency , Subcutaneous Tissue/pathology , Transplantation, Homologous , Tryptophan Hydroxylase/genetics , Tumor Burden
3.
Urology ; 70(5): 893-7, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17919691

ABSTRACT

OBJECTIVES: To examine the impact of the chosen surgical technique and of systematic versus "on-demand" placement of a primary stent on the incidence of urologic complications in adult kidney transplantation. METHODS: Data of 497 consecutive patients undergoing kidney transplantation at a single center were retrospectively analyzed with respect to urologic complications. Three different surgical strategies for the ureteroneocystostomy were compared: (1) transvesical anastomosis with stenting "on demand," (2) extravesical anastomosis with stenting "on demand," and (3) extravesical anastomosis with routine stenting. Nine parameters were evaluated by logistic regression for a possible contribution to the development of urologic complications. RESULTS: Routine placement of a stent significantly reduced the number of urologic complications compared with both transvesical or extravesical anastomoses with stenting "on demand" (20.8% in transvesical "on demand," 17.9% in extravesical "on demand," and 5.8% in extravesical "routine"). Logistic regression analysis revealed that routine stenting versus stenting "on demand" (P = 0.001) and living donor transplantation (P = 0.038) are two independent factors associated with a significantly lower incidence of urologic complications. Although routine stenting was not associated with an increased incidence of urinary tract infections, female gender was the only independent factor associated with this complication (P = 0.001). CONCLUSIONS: Routine stenting of the ureteroneocystostomy is superior to stenting "on demand" in adult kidney transplantation, suggesting that the intraoperative decision of whether to stent is insufficient to avoid urologic complications.


Subject(s)
Kidney Transplantation/methods , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Stents , Urologic Diseases/epidemiology , Urologic Diseases/prevention & control , Female , Humans , Male , Middle Aged , Retrospective Studies , Urologic Surgical Procedures/instrumentation , Urologic Surgical Procedures/methods
4.
Gastroenterology ; 133(2): 608-18, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17681180

ABSTRACT

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is one of the most common causes of liver enzyme elevation in the West. Its prevalence is likely to increase further, paralleling the epidemic increase of the metabolic syndrome. Serotonin degradation by monoamine oxidase A (MAO-A) was recently implicated as an important source of reactive oxygen species. We therefore tested the pathogenetic role of serotonin in a murine model of diet-induced steatohepatitis. METHODS: Wild-type and serotonin-deficient mice, tryptophan hydroxylase 1 (Tph1(-/-)) were fed a choline-methionine-deficient diet for 2 and 6 weeks. MAO-A was inhibited with clorgyline. Steatosis, hepatocyte injury, and hepatic inflammation were assessed by histology, immunohistochemistry, and biochemical analysis. Expression levels of MAO-A and serotonin transporter were analyzed by reverse-transcription polymerase chain reaction and Western blot. Oxidative stress was detected by measuring lipid peroxidation. Mitochondrial damage was determined by electron microscopy and quantification of cytochrome c release. RESULTS: After choline-methionine-deficient diet, Tph1(-/-) mice displayed an equal degree of steatosis, yet reduced hepatocellular injury and less severe inflammation. The difference in these NASH-defining features could be attributed to an increased uptake and catabolism of serotonin, yielding enhanced levels of reactive oxygen species and lipid peroxides, which mediated hepatocellular injury by mitochondrial damage and inflammation. Inhibition of MAO-A reduced hepatocellular damage in wild-type mice. Correspondingly, MAO-A expression was up-regulated significantly in human NASH. CONCLUSIONS: This study provides evidence that serotonin plays a role in the pathogenesis of steatohepatitis, and therefore might represent a novel target for the prevention and treatment of NASH.


Subject(s)
Fatty Liver/metabolism , Hepatitis/etiology , Liver/metabolism , Mitochondria, Liver/metabolism , Oxidative Stress , Serotonin/metabolism , Tryptophan Hydroxylase/metabolism , Adult , Aged , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Choline Deficiency/complications , Clorgyline/pharmacology , Disease Models, Animal , Fatty Liver/complications , Fatty Liver/enzymology , Fatty Liver/genetics , Fatty Liver/pathology , Female , Hepatitis/metabolism , Hepatitis/pathology , Humans , Lipid Peroxidation , Liver/drug effects , Liver/enzymology , Liver/pathology , Male , Methionine/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mitochondria, Liver/drug effects , Mitochondria, Liver/pathology , Monoamine Oxidase/genetics , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/pharmacology , Oxidative Stress/drug effects , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism , Severity of Illness Index , Tryptophan Hydroxylase/deficiency , Tryptophan Hydroxylase/genetics , Up-Regulation
5.
Hepatology ; 45(2): 369-76, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17256748

ABSTRACT

UNLABELLED: Hepatic ischemia and reperfusion (I/R) leads to the formation of leukocyte-platelet aggregates. Upon activation, platelets generate reactive oxygen species and release proapoptotic and proinflammatory mediators as well as growth factors. In cold hepatic ischemia, adhesion of platelets to endothelial cells mediates sinusoidal endothelial cell apoptosis. Furthermore, platelet-derived serotonin mediates liver regeneration. We hypothesized that platelets may contribute to reperfusion injury and repair after normothermic hepatic ischemia. The aim of this study was to assess the impact of platelets in normothermic hepatic I/R injury using models of impaired platelet function and immune thrombocytopenia. Inhibition of platelet function in mice was achieved via clopidogrel feeding. Immune thrombocytopenia was induced via intraperitoneal injection of anti-CD41 antibody. Platelet-derived serotonin was investigated using mice lacking tryptophan hydroxylase 1. Mice were subjected to 60 minutes of partial hepatic ischemia and various time points of reperfusion. Hepatic injury was determined via AST and histological analysis of the necrotic area as well as leukocyte infiltration. Liver regeneration was determined via proliferating cell nuclear antigen and Ki67 immunohistochemistry. Neither inhibition of platelet function nor platelet depletion led to a reduction of I/R injury. Liver regeneration and repair were significantly impaired in platelet-depleted animals. Mice lacking peripheral serotonin were deficient in hepatocyte proliferation, but otherwise displayed normal tissue remodeling. CONCLUSION: Platelets have no direct impact on the pathogenesis of normothermic I/R injury. However, they mediate tissue repair and liver regeneration. Furthermore, platelet-derived serotonin is a mediator of hepatocyte proliferation in the postischemic liver, but has no impact on tissue remodeling.


Subject(s)
Blood Platelets/physiology , Liver Regeneration/physiology , Reperfusion Injury/physiopathology , Serotonin/physiology , Animals , Blood Platelets/pathology , Cell Movement , Cell Proliferation , Cytokines/metabolism , Leukocytes/pathology , Male , Mice , Mice, Knockout , Platelet Count , Reperfusion Injury/metabolism , Temperature , Thrombocytopenia/pathology , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/physiology
6.
Mol Cancer Ther ; 5(6): 1520-9, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16818511

ABSTRACT

Ceramides are sphingolipid second messengers that are involved in the mediation of cell death. There is accumulating evidence that mitochondria play a central role in ceramide-derived toxicity. We designed a novel cationic long-chain ceramide [omega-pyridinium bromide D-erythro-C16-ceramide (LCL-30)] targeting negatively charged mitochondria. Our results show that LCL-30 is highly cytotoxic to SW403 cells (and other cancer cell lines) and preferentially accumulates in mitochondria, resulting in a decrease of the mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-3 and caspase-9. Ultrastructural analyses support the concept of mitochondrial selectivity. Interestingly, levels of endogenous mitochondrial C16-ceramide decreased by more than half, whereas levels of sphingosine-1-phosphate increased dramatically and selectively in mitochondria after administration of LCL-30, suggesting the presence of a mitochondrial sphingosine kinase. Of note, intracellular long-chain ceramide levels and sphingosine-1-phosphate remained unaffected in the cytosolic and extramitochondrial (nuclei/cellular membranes) cellular fractions. Furthermore, a synergistic effect of cotreatment of LCL-30 and doxorubicin was observed, which was not related to alterations in endogenous ceramide levels. Cationic long-chain pyridinium ceramides might be promising new drugs for cancer therapy through their mitochondrial preference.


Subject(s)
Caspases/metabolism , Cell Death/drug effects , Ceramides/pharmacology , Mitochondria/drug effects , Antibiotics, Antineoplastic/pharmacology , Caspase 3 , Caspase 9 , Cations , Ceramides/chemistry , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Cytochromes c/metabolism , Doxorubicin/pharmacology , Drug Combinations , Drug Synergism , Enzyme Activation/drug effects , Humans , Lysophospholipids/metabolism , Membrane Potentials/drug effects , Mitochondria/metabolism , Mitochondrial Membranes/drug effects , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Tumor Cells, Cultured/ultrastructure
7.
Nephrol Dial Transplant ; 21(9): 2563-8, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16702206

ABSTRACT

BACKGROUND: Laparoscopic living kidney nephrectomy is thought to be associated with reduced morbidity, when compared to open nephrectomy. The purpose of this study was to explore the impact of these techniques on donors' clinical outcomes, satisfaction and motivation to donate. METHODS: Clinical outcomes were retrospectively compared in 152 open (n = 71) or laparoscopic (n = 81) donor procedures. Donor satisfaction and motivation were assessed with a self-administered questionnaire. RESULTS: The complication rate was the same with both procedures and the majority of complications were mild. Laparoscopy was significantly less painful and resulted in an insignificantly faster return to active life. More than 80% of the donors volunteered to donate without pressure. Worries about future health status, pain or scars were not important in the decision to donate. Similarly, only 15% considered the surgical procedure as instrumental for their decision. Few donors currently worried about their health with one kidney and more than 95% of the donors in both groups stated that they would give their kidney again. CONCLUSIONS: Living donor nephrectomy is safe, regardless of the procedure used. Although the laparoscopic nephrectomy offers clear short-term benefits over the open nephrectomy, donors' satisfaction was excellent with both surgical approaches. Moreover, the type of procedure did not seem to influence their decision to donate.


Subject(s)
Kidney Failure, Chronic/surgery , Kidney Transplantation/psychology , Laparoscopy , Laparotomy , Living Donors/psychology , Motivation , Nephrectomy/methods , Adult , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Satisfaction , Quality of Life , Retrospective Studies , Surveys and Questionnaires , Switzerland , Treatment Outcome
8.
Am J Transplant ; 5(11): 2605-10, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16212618

ABSTRACT

Widespread application of cadaveric split or living donor liver transplantation bears considerable potential to increase the pool of available organs and thus alleviate the problem of organ shortage. Although splitting of a cadaveric liver into two grafts for adult recipients can be performed successfully, sufficient function of undersized grafts is a major concern. To minimize the risk for living donors, transplant surgeons aim at procuring the least necessary liver volume, also leading to potentially small grafts. When small partial grafts are unable to meet the functional demands, the recipients can develop a so-called small-for-size syndrome (SFSS). There is currently limited data on the pathogenesis of SFSS, with clinical studies mainly focusing on portal hyperperfusion. Additional aspects include graft-related factors such as functional and regenerative capacity, as well as recipient-related factors, such as overall health status and severity of cirrhosis. However, there is currently no consensus on the definition of SFSS. We propose a novel definition, based on simple clinical criteria, which divides the syndrome into either nonfunction or dysfunction of a small graft after the exclusion of other causes. This definition should ease comparability of future clinical trials, and thus improve understanding of the pathogenesis of SFSS.


Subject(s)
Body Constitution , Hepatectomy/methods , Liver Transplantation/methods , Tissue and Organ Harvesting/methods , Cadaver , Humans , Liver/anatomy & histology , Liver Circulation , Liver Regeneration , Patient Selection , Tissue Donors/supply & distribution
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