Effects of methylmercury on electric organ discharges in the weak electric fish Gymnotus sylvius

Methylmercury (MeHg) is present in the environment because of natural and anthropogenic causes. MeHg can reach the central nervous system (CNS) and cause neurological damage in humans and animals. Electric organ discharges (EODs) in the weak electric fish Gymnotus sylvius are produced by the electric organ and modulated by the CNS. These discharges are used for electrolocation and communication. The purpose of the present study was to investigate the effects of dietary MeHg exposure on EOD rate in G. sylvius. An oscilloscope was used to record the EOD rate. Two treatments were investigated: chronic MeHg administration (4 μg/kg MeHg every 2 days, with a total of nine dietary exposures to MeHg) and acute MeHg administration (a single dose of 20 μg/kg MeHg). The control data for both treatments were collected every 2 days for 18 days, with a total of nine sessions (day 1 until day 18). Data of fish exposed to MeHg were collected every 2 days, totaling nine sessions (day 19 until day 36). Chronic treatment significantly increased the EOD rate in G. sylvius (p<.05), especially with the final treatment (day 32 until day 36). Acute treatment resulted in an initial increase in the EOD rate, which was maintained midway through the experiment (day 26 until day 30 p<.05). The present study provides the first insights into the effects of MeHg on EODs in weak electric fish. The EOD rate is a novel response of the fish to MeHg administration.

Protective actions of melatonin against heart damage during chronic Chagas disease

Chronic cardiomyopathy is the most important clinical form of Chagas disease, and it is characterised by myocarditis that is associated with fibrosis and organ dysfunction. Alternative treatment options are important tools to modulate host immune responses. The main goal of this work was to evaluate the anti-inflammatory actions of melatonin during the chronic phase of Chagas disease. TNF-α, IL-10 and nitrite concentrations were evaluated as predictive factors of immune modulation. Creatine phosphokinase-MB (CK-MB), cardiac inflammatory foci and heart weight were assessed to evaluate the efficacy of the melatonin treatment. Male Wistar rats were infected with 1 × 105 blood trypomastigotes of the Y strain of Trypanosoma cruzi and kept untreated for 60 days to mimic chronic infection. After this period, the rats were orally treated with melatonin 50 mg/kg/day, and the experiments were performed 90, 120, and 180 days post-infection. Melatonin treatment significantly increased the concentration of IL-10 and reduced the concentrations of NO and TNF-α produced by cardiomyocytes. Furthermore, it led to decreased heart weight, serum CK-MB levels and inflammatory foci when compared to the untreated and infected control groups. We conclude that melatonin therapy is effective at protecting animals against the harmful cardiac inflammatory response that is characteristic of chronic T. cruzi infection. © 2013 Elsevier B.V. All rights reserved.

Application of poly(epsilon-caprolactone) nanoparticles containing atrazine herbicide as an alternative technique to control weeds and reduce damage to the environment

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cytotoxic Effects of Thiamethoxam in the Midgut and Malpighian Tubules of Africanized Apis mellifera (Hymenoptera: Apidae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Protective effect of bixin on carbon tetrachloride-induced hepatotoxicity in rats

Background: The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl4) in rats.Results: The animals were divided into four groups with six rats in each group. CCl4 (0.125 mL kg(-1) body wt.) was injected intraperitoneally, and bixin (5.0 mg kg(-1) body wt.) was given by gavage 7 days before the CCl4 injection. Bixin prevented the liver damage caused by CCl4, as noted by the significant decrease in serum aminotransferases release. Bixin protected the liver against the oxidizing effects of CCl4 by preventing a decrease in glutathione reductase activity and the levels of reduced glutathione and NADPH. The peroxidation of membrane lipids and histopathological damage of the liver was significantly prevented by bixin treatment.Conclusion: Therefore, we can conclude that the protective effect of bixin against hepatotoxicity induced by CCl4 is related to the antioxidant activity of the compound.

Natural killer activity in a medium-term multi-organ bioassay for carcinogenesis

Natural killer (NK) cell activity was evaluated after the initiation and promotion steps in a medium-term multi-organ bioassay for carcinogenesis. NK cell activity was assessed in vitro by Cr51 release assay at the 4th and 30th weeks of the experiment. Male Wistar rats were sequentially initiated with N-diethylnitrosamine (DEN i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN drinking water), N-methyl-N-nitrosourea (MNU i.p.), dihydroxy-di-N-propylnitrosamine (DHPN drinking water) and N,N'-dimethylhydrazine (DMH s.c.) at subcarcinogenic doses for 4 weeks (DMBDD initiation). One group was evaluated at the 4th week and the other was maintained without any further treatment until the 30th week. Two initiated groups were exposed through the diet to 2-acetylaminofluorene (2-AAF) or phenobarbital (PB), from the 6th until the 30th week. Five additional groups were studied to evaluate the effects of each initiator on NK activity. All groups submitted to initiation only, initiation plus promotion, or promotion only, developed significantly more preneoplastic lesions than the untreated control group. The main target organs for tumor development in the initiated animals were the liver and the colon, irrespective of treatment with 2-AAF or PB. NK cell activity was not affected by exposure to genotoxic carcinogens after initiation, at the 4th week. Treatments only with PB or 2-AAF did not change NK cell activity. However, decreased NK cell activity was registered in the group only initiated with DMBDD and in the group given DMBDD+2-AAF. This late depression of NK cell activity at the 30th week could be related to the production of suppressing molecules by the tumor cells.

Evaluation of DNA damage and lipoperoxidation of propofol in patients undergoing elective surgery

Inhaled anaesthetics have been studied regarding their genotoxic and mutagenic potential in vivo. Propofol differs from volatile anaesthetics because it does not show mutagenic effects and it has been reported to be an antioxidant. However, there are no studies with propofol and genotoxicity in vivo. The study aimed to evaluate the hypothesis that propofol is not genotoxic and it inhibits lipid peroxidation [malondialdehyde (MDA)] in patients undergoing propofol anaesthesia. ASA physical status I patients scheduled for elective surgery, lasting at least 90 min, were enrolled in this study. Initially, the estimated plasma concentration of propofol was targeted at 4 microg ml(-1) and then maintained at 2-4 microg ml(-1) until the end of surgery. Haemodynamic data were determined at baseline (before premedication) and in conjunction with target-controlled infusion of propofol: after tracheal intubation, 30, 60 and 90 min after anaesthesia induction and at the end of the surgery. Venous blood samples were collected at baseline, after tracheal intubation, at the end of the surgery and on the postoperative first day for evaluating DNA damage in white blood cells (WBCs), by comet assay, and MDA levels. Haemodynamic data did not differ among times. No statistically significant differences were observed for the levels of DNA damage in WBCs, nor in plasma MDA, among the four times. Propofol does not induce DNA damage in WBCs and does not alter MDA in plasma of patients.

Cytotoxic effects of neem oil in the midgut of the predator Ceraeochrysa claveri

Studies of morphological and ultrastructural alterations in target organs have been useful for evaluating the sublethal effects of biopesticides regarded as safe for non-target organisms in ecotoxicological analyses. One of the most widely used biopesticides is neem oil, and its safety and compatibility with natural enemies have been further clarified through bioassays performed to analyze the effects of indirect exposure by the intake of poisoned prey. Thus, this study examined the cellular response of midgut epithelial cells of the adult lacewing, Ceraeochrysa claveri, to neem oil exposure via intake of neem oil-contaminated prey during the larval stage. C. claveri larvae were fed Diatraea saccharalis eggs treated with neem oil at concentrations of 0.5%, 1% and 2% throughout the larval stage. The adult females obtained from these treatments were used at two ages (newly emerged and at the start of oviposition) in morphological and ultrastructural analyses. Neem oil was found to cause pronounced cytotoxic effects in the adult midgut, such as cell dilation, emission of cytoplasmic protrusions, cell lysis, loss of integrity of the cell cortex, dilation of cisternae of the rough endoplasmic reticulum, swollen mitochondria, vesiculated appearance of the Golgi complex and dilated invaginations of the basal labyrinth. Epithelial cells responded to those injuries with various cytoprotective and detoxification mechanisms, including increases in cell proliferation, the number of calcium-containing cytoplasmic granules, and HSP 70 expression, autophagic processes and the development of smooth endoplasmic reticulum, but these mechanisms were insufficient for recovery from all of the cellular damage to the midgut. This study demonstrates that neem oil exposure impairs the midgut by causing sublethal effects that may affect the physiological functions of this organ, indicating the importance of studies of different life stages of this species and similar species to evaluate the safe and compatible integrated use of biopesticides.

Synthesis and Photodynamic Effect of New Highly Photostable Decacationically Armed [60]- and [70]Fullerene Decaiodide Monoadducts To Target Pathogenic Bacteria and Cancer Cells

Novel water-soluble decacationically armed C-60 and C-70 decaiodide monoadducts, C-60- and C-70[>M(C3N6+C3)(2)], were synthesized, characterized, and applied as photosensitizers and potential nano-PDT agents against pathogenic bacteria and cancer cells. A high number of cationic charges per fullerene cage and H-bonding moieties were designed for rapid binding to the anionic residues displayed on the outer parts of bacterial cell walls. In the presence of a high number of electron-donating iodide anions as parts of quaternary ammonium salts in the arm region, we found that C-70[>M(C3N6+C3)(2)] produced more HO center dot than C-60[>M(C3N6+C3)(2)], in addition to O-1(2). This finding offers an explanation of the preferential killing of Gram-positive and Gram-negative bacteria by C-60[>M(C3N6+C3)(2)] and C-70[>M(C3N6+C3)(2)], respectively. The hypothesis is that O-1(2) can diffuse more easily into porous cell walls of Gram-positive bacteria to reach sensitive sites, while the less permeable Gram-negative bacterial cell wall needs the more reactive HO center dot to cause real damage.

Rates of Change in the Visual Field and Optic Disc in Patients with Distinct Patterns of Glaucomatous Optic Disc Damage

Purpose: To investigate the rate of visual field and optic disc change in patients with distinct patterns of glaucomatous optic disc damage. Design: Prospective longitudinal study. Participants: A total of 131 patients with open-angle glaucoma with focal (n = 45), diffuse (n = 42), and sclerotic (n = 44) optic disc damage. Methods: Patients were examined every 4 months with standard automated perimetry (SAP, SITA Standard, 24-2 test, Humphrey Field Analyzer, Carl Zeiss Meditec, Dublin, CA) and confocal scanning laser tomography (CSLT, Heidelberg Retina Tomograph, Heidelberg Engineering GmbH, Heidelberg, Germany) for a period of 4 years. During this time, patients were treated according to a predefined protocol to achieve a target intraocular pressure (IOP). Rates of change were estimated by robust linear regression of visual field mean deviation (MD) and global optic disc neuroretinal rim area with follow-up time. Main Outcome Measures: Rates of change in MD and rim area. Results: Rates of visual field change in patients with focal optic disc damage (mean -0.34, standard deviation [SD] 0.69 dB/year) were faster than in patients with sclerotic (mean - 0.14, SD 0.77 dB/year) and diffuse (mean + 0.01, SD 0.37 dB/year) optic disc damage (P = 0.003, Kruskal-Wallis). Rates of optic disc change in patients with focal optic disc damage (mean - 11.70, SD 25.5 x 10(-3) mm(2)/year) were faster than in patients with diffuse (mean -9.16, SD 14.9 x 10(-3) mm(2)/year) and sclerotic (mean -0.45, SD 20.6 x 10(-3) mm(2)/year) optic disc damage, although the differences were not statistically significant (P = 0.11). Absolute IOP reduction from untreated levels was similar among the groups (P = 0.59). Conclusions: Patients with focal optic disc damage had faster rates of visual field change and a tendency toward faster rates of optic disc deterioration when compared with patients with diffuse and sclerotic optic disc damage, despite similar IOP reductions during follow-up. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012; 119: 294-303 (C) 2012 by the American Academy of Ophthalmology.

Radiation induced apoptosis and initial DNA damage are inversely related in locally advanced breast cancer patients

[EN] Background: DNA-damage assays, quantifying the initial number of DNA double-strand breaks induced by radiation, have been proposed as a predictive test for radiation-induced toxicity. Determination of radiation-induced apoptosis in peripheral blood lymphocytes by flow cytometry analysis has also been proposed as an approach for predicting normal tissue responses following radiotherapy. The aim of the present study was to explore the association between initial DNA damage, estimated by the number of double-strand breaks induced by a given radiation dose, and the radio-induced apoptosis rates observed. Methods: Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radio-induced apoptosis at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results: Radiation-induced apoptosis increased in order to radiation dose and data fitted to a semi logarithmic mathematical model. A positive correlation was found among radio-induced apoptosis values at different radiation doses: 1, 2 and 8 Gy (p < 0.0001 in all cases). Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). A statistically significant inverse correlation was found between initial damage to DNA and radio-induced apoptosis at 1 Gy (p = 0.034). A trend toward 2 Gy (p = 0.057) and 8 Gy (p = 0.067) was observed after 24 hours of incubation. Conclusions: An inverse association was observed for the first time between these variables, both considered as predictive factors to radiation toxicity.

Sintesi di nuovi derivati tri-componente per target photodynamic therapy della neoplasia prostatica

Therapies for the treatment of prostate cancer show several limitations, especially when the cancer metastasizes or acquires resistance to treatment. In addition, most of the therapies currently used entails the occurrence of serious side effects. A different therapeutic approach, more selective and less invasive with respect either to radio or to chemotherapy, is represented by the photodynamic therapy (PDT). The PDT is a treatment that makes use of photosensitive drugs: these agents are pharmacologically inactive until they are irradiated with light at an appropriate wavelength and in the presence of oxygen. The drug, activated by light, forms singlet oxygen, a highly reactive chemical species directly responsible for DNA damage, thus of cell death. In this thesis we present two synthetic strategies for the preparation of two new tri-component derivatives for photodynamic therapy of advanced prostate cancer, namely DRPDT1 and DRPDT2. Both derivatives are formed by three basic elements covalently bounded to each other: a specific ligand with high affinity for the androgen receptor, a suitably chosen spacer molecule and a photoactivated molecule. In particular, DRPDT2 differs from DRPDT1 from the nature of the AR ligand. In fact, in the case of DRPDT2 we used a synthetically engineered androgen receptor ligand able to photo-react even in the absence of oxygen, by delivering NO radical. The presence of this additional pharmacophore, together with the porphyrin, may ensure an additive/synergistic effect to the photo-stimulated therapy, which than may act both in the presence of oxygen and in hypoxic conditions. This approach represents the first example of multimodal photodynamic therapy for prostate cancer.

In vitro characterisation and expansion of human regulatory T cells for their in vivo application in the induction of tolerance in haematopoietic stem cell and solid organ transplantation

Solid organ transplantation (SOT) is considered the treatment of choice for many end-stage organ diseases. Thus far, short term results are excellent, with patient survival rates greater than 90% one year post-surgery, but there are several problems with the long term acceptance and use of immunosuppressive drugs. Hematopoietic Stem Cells Transplantation (HSCT) concerns the infusion of haematopoietic stem cells to re-establish acquired and congenital disorders of the hematopoietic system. The main side effect is the Graft versus Host Disease (GvHD) where donor T cells can cause pathology involving the damage of host tissues. Patients undergoing acute or chronic GvHD receive immunosuppressive regimen that is responsible for several side effects. The use of immunosuppressive drugs in the setting of SOT and GvHD has markedly reduced the incidence of acute rejection and the tissue damage in GvHD however, the numerous adverse side effects observed boost the development of alternative strategies to improve the long-term outcome. To this effect, the use of CD4+CD25+FOXP3+ regulatory T cells (Treg) as a cellular therapy is an attractive approach for autoimmunity disease, GvHD and limiting immune responses to allograft after transplantation. Treg have a pivotal role in maintaining peripheral immunological tolerance, by preventing autoimmunity and chronic inflammation. Results of my thesis provide the characterization and cell processing of Tregs from healthy controls and patients in waiting list for liver transplantation, followed by the development of an efficient expansion-protocol and the investigation of the impact of the main immunosuppressive drugs on viability, proliferative capacity and function of expanded cells after expansion. The conclusion is that ex vivo expansion is necessary to infuse a high Treg dose and although many other factors in vivo can contribute to the success of Treg therapy, the infusion of Tregs during the administration of the highest dose of immunosuppressants should be carefully considered.

Mechanistic study of cell death induction by O 6-methylating agents, focusing on the role of homologous recombination as a molecular target for sensitization of tumor cells to chemotherapeutic alkylating agents

Chemotherapeutic SN1‑methylating agents are important anticancer drugs. They induce several covalent modifications in the DNA, from which O6‑methylguanine (O6MeG) is the main toxic lesion. In this work, different hypotheses that have been proposed to explain the mechanism of O6MeG‑triggered cell death were tested. The results of this work support the abortive processing model, which states that abortive post‑replicative processing of O6MeG‑driven mispairs by the DNA mismatch repair (MMR) machinery results in single‑strand gaps in the DNA that, upon a 2nd round of DNA replication, leads to DNA double‑strand break (DSB) formation, checkpoint activation and cell death. In this work, it was shown that O6MeG induces an accumulation of cells in the 2nd G2/M‑phase after treatment. This was accompanied by an increase in DSB formation in the 2nd S/G2/M‑phase, and paralleled by activation of the checkpoint kinases ATR and CHK1. Apoptosis was activated in the 2nd cell cycle. A portion of cells continue proliferating past the 2nd cell cycle, and triggers apoptosis in the subsequent generations. An extension to the original model is proposed, where the persistence of O6MeG in the DNA causes new abortive MMR processing in the 2nd and subsequent generations, where new DSB are produced triggering cell death. Interestingly, removal of O6MeG beyond the 2nd generation lead to a significant, but not complete, reduction in apoptosis, pointing to the involvement of additional mechanisms as a cause of apoptosis. We therefore propose that an increase in genomic instability resulting from accumulation of mis‑repaired DNA damage plays a role in cell death induction. Given the central role of DSB formation in toxicity triggered by chemotherapeutic SN1‑alkylating agents, it was aimed in the second part of this thesis to determine whether inhibition of DSB repair by homologous recombination (HR) or non‑homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioblastoma cells to these agents. The results of this work show that HR down‑regulation in glioblastoma cells impairs the repair of temozolomide (TMZ)‑induced DSB. HR down‑regulation greatly sensitizes cells to cell death following O6‑methylating (TMZ) or O6‑chlorethylating (nimustine) treatment, but not following ionizing radiation. The RNAi mediated inhibition in DSB repair and chemo‑sensitization was proportional to the knockdown of the HR protein RAD51. Chemo‑sensitization was demonstrated for several HR proteins, in glioma cell lines proficient and mutated in p53. Evidence is provided showing that O6MeG is the primary lesion responsible for the increased sensitivity of glioblastoma cells following TMZ treatment, and that inhibition of the resistance marker MGMT restores the chemo‑sensitization achieved by HR down‑regulation. Data are also provided to show that inhibition of DNA‑PK dependent NHEJ does not significantly sensitized glioblastoma cells to TMZ treatment. Finally, the data also show that PARP inhibition with olaparib additionally sensitized HR down‑regulated glioma cells to TMZ. Collectively, the data show that processing of O6MeG through two rounds of DNA replication is required for DSB formation, checkpoint activation and apoptosis induction, and that O6MeG‑triggered apoptosis is also executed in subsequent generations. Furthermore, the data provide proof of principle evidence that down‑regulation of HR is a reasonable strategy for sensitizing glioma cells to killing by O6‑alkylating chemotherapeutics.

Untersuchungen zum Einfluss des HMG-CoA-Reduktase-Inhibitors Lovastatin auf die Toxizität ionisierender Strahlung sowie des Anthrazyklinderivats Doxorubicin im Mausmodell

Hintergund: HMG-CoA-Reduktase-Inhibitoren (Statine) sind klinisch etablierte Cholesterinsenker. Über die Inhibition der intrinsischen Cholesterinbiosynthese hinaus zeigen sie sogenannte pleiotrope biologische Effekte. Ein Großteil dieser Wirkungen wird auf die Inhibition kleiner Ras homologer GTPasen (Rho GTPasen) zurückgeführt. In vitro schützt das Statinderivat Lovastatin (Lova) primäre humane Endothelzellen vor der Zytotoxizität von ionisierender Strahlung (IR) und dem Krebsmedikament Doxorubicin (Doxo). Zielsetzung: Die Relevanz dieser Befunde für ein in vivo Mausmodell sollte in der vorliegenden Arbeit überprüft werden. Dafür wurden BALB/c-Mäuse mit IR oder Doxo behandelt und der Einfluss einer Kobehandlung mit Lova auf verschiedene Toxizitätsendpunkte untersucht (24 h nach einer einzelnen hohen Dosis IR (i), 14 Tage nach zwei geringen Dosen IR (ii), 48 h nach einer einzelnen hohen Dosis Doxo (iii), sowie 8 Tage nach drei niedrigen Dosen Doxo (iv)). Eine mögliche gleichzeitige Protektion von Tumorzellen durch die Statingabe wurde in einem Xenotransplantationsexperiment überprüft (v), in dem das gleiche Behandlungsschema wie bei iv angewendet wurde. Ergebnisse: Es konnte gezeigt werden, dass eine Statinbehandlung Normalgewebe vor Doxo- und IR-induzierter Toxizität schützt, ohne gleichzeitig protektiv auf transformierte Zellen zu wirken. Dieser Effekt ist wahrscheinlich von einer Inhibition der kleinen GTPasen Rac1 und RhoA abhängig und einer daraus folgenden Modifizierung der DNA-Schadensantwort. i: Die Statinvorbehandlung der Mäuse hatte keinen Einfluss auf die Bildung von initialen IR-induzierten DNA-Doppelstrangbrüchen (DSB) in der Leber. Die Lova-Behandlung wirkte sich jedoch auf IR-induzierte Stressantworten aus, was sich in einer Minderung der Expression von Inflammations- und Fibrosesurrogatmarkern in Leber und Darm widerspiegelte. ii: In der Lunge der Tiere wurde ein Anstieg von molekularen Inflammations- und Fibrosesurrogatmarkern detektiert, der bei Statinkobehandlung ausblieb. Zudem verhinderte die Kobehandlung mit Lova eine IR-induzierte Abnahme der Thrombozytenzahl, ohne sich auf die durch IR verringerte Leukozytenzahl im Blut auszuwirken. iii: Die Verabreichung einer hohen Dosis Doxo induzierte DSB-Formation in der Leber. Die Statinvorbehandlung reduzierte deren Menge um ca. 50 %. Dieser genoprotektive Effekt war unabhängig von der Entstehung reaktiver Sauerstoffspezies sowie einer Änderung des Doxo-Imports oder Exports. Die Expression von proinflammatorischen und profibrotischen Genen fiel besonders in der Leber und im Herzen durch die Lova-Kobehandlung geringer aus, als in der nur mit Doxo behandelten Gruppe. Zudem verringerte Lova die durch Doxo induzierte Hochregulation von für den AP1-Komplex kodierenden Genen sowie von Zellzykluskontrollfaktoren. Die Lova-Vorbehandlung führte darüber hinaus im Herzen zu einem reduzierten mRNA-Spiegel der Topoisomerasen II α und β. iv: Es konnten schwere Herz- und Leberschäden detektiert werden (gemessen an Gldh-, Gpt- sowie cTn-I-Serumkonzentrationen), die bei einer Kobehandlung mit dem Statin nicht auftraten. Die Lova-Kobehandlung verhinderte außerdem eine durch die Doxo-Behandlung verringerte Leukozytenzahl. Molekulare Marker für frühe fibrotische Ereignisse, sowie für Inflammation und Hypertrophie waren in der Leber und im Herzen nach der Doxo-Behandlung erhöht. Das Statin war auch hier in der Lage, diese toxischen Wirkungen des Anthrazyklins zu mindern. Auch die Doxo-induzierte Expression von Surrogatmarkern für Zellantworten auf oxidativen Stress wurde in der Leber abgeschwächt. In der Leber und im Herzen wiesen die mit Doxo behandelten Tiere höhere mRNA Spiegel von an Zellzykluskontrolle beteiligten Faktoren sowie von DNA-Reparatur und Fremdstoffmetabolismus assoziierten Genen auf. Am stärksten wurde die Expression von Topoisomerase II alpha - ein molekularer Marker für Zellproliferation und bedeutsame Zielstruktur von Doxo - in der Leber hochreguliert. Die Statin-Kobehandlung verhinderte all diese Doxo-induzierten Expressionsänderungen. Im Gegensatz zur Leber wurde die Top2a-mRNA Menge im Herzen durch die Doxo-Applikation reduziert. Auch hier bewirkte die Kobehandlung mit dem Statin, dass die Expression nahe dem Kontrollniveau blieb. v: Die Kobehandlung mit Lova führte zu keinem Schutz der Tumorzellen vor Doxo, sondern erhöhte sogar dessen antineoplastisches Potential.rnFazit: Die Erkenntnisse aus vorhergegangenen in vitro Versuchen konnten zum großen Teil auf die in vivo Situation im Mausmodell übertragen werden. Sie stehen im Einklang mit Ergebnissen anderer Gruppen, welche die Inhibition kleiner GTPasen mit einer geringeren, durch zytotoxische Substanzen induzierten, Inflammation und Fibrose korrelieren konnten. Eine Kobehandlung mit Lova während einer Krebstherapie erscheint somit als vielversprechende Möglichkeit Doxo- oder IR-induzierte Nebenwirkungen auf Normalgewebe zu mildern.