The impact of in vivo and in vitro exposure to base analogue 5-FU on the level of DNA damage in haemocytes of freshwater mussels Unio pictorum and Unio tumidus

2014 ◽  
Vol 191 ◽  
pp. 145-150 ◽  
Author(s):  
Zoran Gačić ◽  
Stoimir Kolarević ◽  
Karolina Sunjog ◽  
Margareta Kračun-Kolarević ◽  
Momir Paunović ◽  
...  
Keyword(s):  
Dna Damage ◽  
Freshwater Mussels ◽  
In Vitro Exposure ◽  
Unio Tumidus ◽  
The Impact ◽  
Unio Pictorum

Measurement of Individual p53-Specific Damage Formation and Repair Following In Vitro Exposure of Peripheral Mononuclear Cells to Melphalan May Predict Clinical Outcome in Patients with Multiple Myeloma (MM) Subsequently Treated with High Dose Melphalan (HDM) and Autologous Blood Stem Cell Transplantation (ASCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1167-1167
Author(s):  
Meletios A. Dimopoulos ◽  
V. L. Souliotis ◽  
A. Anagnostopoulos ◽  
A. Pouli ◽  
I. Baltadakis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Clinical Outcome ◽  
Dna Adducts ◽  
P53 Gene ◽  
Peripheral Blood Lymphocytes ◽  
P Value ◽  
In Vitro Measurements ◽  
In Vitro Exposure

Abstract Introduction: Melphalan reacts extensively with cellular DNA. DNA monoadducts (MA) and interstrand cross-links (ICL) are the main events occurring after drug exposure. Subsequently, complex pathways contribute to repair of DNA lesions. We have previously showed that individual repairing capacity in p53 gene in vivo varied up to 16-fold among pts with MM receiving HDM, while increased DNA damage and slower repairing capacity correlated with improved clinical outcome (Dimopoulos et al, JCO 2005). We examine here if measurement of gene-specific DNA damage formation and repair after in vitro exposure of peripheral blood lymphocytes (PBL) to melphalan correlates with in vivo DNA damage and repair after exposure to HDM and if in vitro findings correlate with subsequent clinical outcome. Methods: Gene-specific MA and ICL formation and repair in the p53 gene were measured in PBL from MM pts, candidates for HDM (200mg/m2) and ASCT following in vitro exposure to 10 μg/ml melphalan for 1 h at 37°C. Measurements were performed 0, 2, 8 and 24 hours after in vitro exposure to melphalan. The same measurements were performed in vivo at 0, 2, 8 and 24 hours after treatment with HDM as previously described. Individual amounts of each type of DNA adducts over time (0–24h) were assessed by the area under the curve (AUC) during the whole experiment. Response after HDM was assessed according to the EBMT criteria. Measurements of DNA adducts after in vivo and in vitro treatment were correlated by the correlation-coefficient method. Results: So far, in 25 pts in vitro measurements have been performed and in 15 pts in vivo measurements and correlations with clinical outcome were made as well. One pt was treated in relapse, 3 patients had primary refractory disease and 11 were in remission. Individual kinetics of melphalan-induced DNA damage formation and repair varied remarkably among patients both for the in vivo and in vitro measurements. A strong correlation between in vivo and in vitro measurements was found (p≤0.02 for all measurements). Patients were separated into 2 groups. Responders i.e. patients who achieved CR or PR (n=10) after HDM and non responders i.e. pts who were rated as SD or PD (n=5). A significant correlation of clinical response with p53 gene-specific damage formation and repair was found in both in vitro and in vivo data. AUC (adducts/106 nucleotides x h) Total adducts (mean) Interstrand crosslinks (mean) Monoadducts (mean) Responders 919 +/− 215 303,9 +/− 108 616 +/− 154 In vitro Non responders 495 +/− 220 161,3 +/− 80,8 336 +/− 154 p-value 0,003 0,02 0,006 Responders 257 +/− 76 29,4 +/− 8,5 229 +/− 68 In vivo Non responders 122 +/− 91 13,8 +/− 4,6 112,8 +/− 82 p-value 0,009 0,002 0,01 Conclusion: Our results suggests that individuals with slower repairing capacity of the in vitro melphalan-induced p53 damage in peripheral blood lymphocytes have improved clinical outcome following subsequent treatment with HDM. We believe that our ongoing study may help select patients with MM who are more likely to benefit from HDM.

Cellular Senescence Contributes to the Outcome of Lymphoma Chemotherapy by Cell-Autonomous and Paracrine Immune Mechanisms

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3617-3617
Author(s):  
Jan Dörr ◽  
Yong Yu ◽  
Bernd Dörken ◽  
Clemens A. Schmitt
Keyword(s):  
Dna Damage ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Cell Interactions ◽  
Brdu Incorporation ◽  
Tumor Site ◽  
Immune Cell Subsets ◽  
The Impact

Abstract Introduction: Premature senescence reflects an acutely inducible, irreversible growth arrest as a cellular response to stresses such as oncogenic activation and DNA damage, including chemotherapeutic anticancer agents. Senescence complements apoptosis as a tumor suppressive and therapeutic effector principle, but whether a selective disruption of the senescence machinery impairs treatment outcome is unknown. Moreover, function and fate of senescent tumor cells within the tumor site remain unclear. Here, we analyze the impact of defined genetic alterations, i.e. Bcl2 overexpression (blocking apoptosis), deletion of the histone H3 lysine 9 methyltransferase Suv39h1 (controlling senescence), and conditional expression of p53 (mediating both apoptosis and senescence), on therapy-induced senescence (TIS) in the Eμ-myc mouse lymphoma model with specific emphasis on immunological tumor-host and growth-modulating senescent/non-senescent cell interactions as a consequence of TIS in vitro and in vivo. Methods: Lymphoma cells (LCs) of various genetic backgrounds were retrovirally transduced with the bcl2 gene to study TIS in the absence of drug-induced apoptosis. Bcl2-protected LCs were treated with the DNA damaging anticancer agent adriamycin in vitro, or were exposed to the alkylating agent cyclophosphamide upon lymphoma formation in normal immunocompetent mice in vivo. TIS was detected by staining for senescence-associated β-galactosidase activity (SA-β-gal) and other senescence-related markers, including Ki67 and BrdU incorporation. To study tumor-host cell interactions, isolated normal splenocytes were co-incubated with proliferating or senescent LCs in vitro. Immunophenotyping was carried out with antibodies specific for macrophages, granulocytes, natural killer cells and T-lymphocytes. Cytokine production was measured by protein arrays. Results: Senescent LCs engage in cell-cell interactions with different immune cell subsets, in particular macrophages, granulocytes and T-cells in vitro. Fluorescence microscopy reveals that macrophages engulf LCs after they entered TIS. In vivo, TIS correlates with the quantitative attraction of immune cell populations to the tumor site and subsequent clearing of senescent cells. Ongoing mechanistic studies on underlying ligand/receptor interactions will be reported at the meeting. TIS cells exhibit a specific pro-inflammatory secretory profile whose functional impact on tumor and bystander cells is currently being investigated. Importantly, this profile is distinguishable from cytokine profiles of senescence-compromised Suv39h1- or p53-deficient lymphomas, and, thus, reflects a senescence - rather than a DNA damage-associated secretory response. Discussion: The study unveils a functional interaction of senescent LCs with different immune cell subsets in vitro and in vivo. The cytokine arrays show that senescent cells produce a specific secretory profile, which might stimulate immune cell attraction. Therefore, immune cells could be recruited to lymphomas in vivo specifically after TIS with the potential to clear senescent – and possibly non-senescent – cells from the tumor site. The data demonstrate genetically that senescence is a beneficial effector principle of DNA damaging chemotherapy and encourage further exploration of this program to limit cancer expansion in vivo.

scholarly journals The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

2019 ◽  
Vol 93 (11) ◽  
pp. 3345-3366 ◽  
Author(s):  
Mateja Sborchia ◽  
Eric G. De Prez ◽  
Marie-Hélène Antoine ◽  
Lucie Bienfait ◽  
Radek Indra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Renal Injury ◽  
Aristolochic Acid ◽  
Underlying Mechanism ◽  
Dna Adduct ◽  
Gas Chromatography Mass Spectrometry ◽  
Primary Mouse ◽  
The Impact

Abstract Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(−/−) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography–mass spectrometry (GC–MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice and exposed them to AAI in vitro (50 µM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(−/−) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(−/−) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

scholarly journals DNA damage and repair process in earthworm after in-vivo and in vitro exposure to soils irrigated by wastewaters

2007 ◽  
Vol 148 (1) ◽  
pp. 141-147 ◽  
Author(s):  
Min Qiao ◽  
Ying Chen ◽  
Chun-Xia Wang ◽  
Zijian Wang ◽  
Yong-Guan Zhu
Keyword(s):  
Dna Damage ◽  
Repair Process ◽  
Dna Damage And Repair ◽  
In Vitro Exposure

Curcumin-containing Silver Nanoparticles prevent carbon tetrachlorideinduced hepatotoxicity in mice

2020 ◽  
Vol 23 ◽  
Author(s):  
Hossam Ebaid ◽  
Mohamed Habila ◽  
Iftekhar Hassan ◽  
Jameel Al-Tamimi ◽  
Mohamed S. Omar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Silver Nanoparticles ◽  
Nuclear Dna ◽  
Liquid Paraffin ◽  
Tail Length ◽  
Hepatic Tissue ◽  
Tissue Destruction ◽  
Group 2 ◽  
The Impact

Background: Hepatotoxicity remains an important clinical challenge. Hepatotoxicity observed in response to toxins and hazardous chemicals may be alleviated by delivery of the curcumin in silver nanoparticles (AgNPs-curcumin). In this study, we examined the impact of AgNPs-curcumin in a mouse model of carbon tetrachloride (CCl4)-induced hepatic injury. Methods: Male C57BL/6 mice were divided into three groups (n=8 per group). Mice in group 1 were treated with vehicle control alone, while mice in Group 2 received a single intraperitoneal injection of 1 ml/kg CCl4 in liquid paraffin (1:1 v/v). Mice in group 3 were treated with 2.5 mg/kg AgNPs-curcumin twice per week for three weeks after the CCl4 challenge. Results: Administration of CCL4 resulted in oxidative dysregulation, including significant reductions in reduced glutathione and concomitant elevations in the level of malondialdehyde (MDA). CCL4 challenge also resulted in elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT); these findings were associated with the destruction of hepatic tissues. Treatment with AgNPs-curcumin prevented oxidative imbalance, hepatic dysfunction, and tissue destruction. A comet assay revealed that CCl4 challenge resulted in significant DNA damage as documented by a 70% increase in nuclear DNA tail-length; treatment with AgNPs-curcumin inhibited the CCL4-mediated increase in nuclear DNA tail-length by 34%. Conclusion: Administration of AgNPs-curcumin resulted in significant antioxidant activity in vivo. This agent has the potential to prevent the hepatic tissue destruction and DNA damage that results from direct exposure to CCL4.

A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage

2019 ◽  
Vol 19 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Yang Liu ◽  
Jingyin Zhang ◽  
Shuyun Feng ◽  
Tingli Zhao ◽  
Zhengzheng Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Cyclin D ◽  
Dna Relaxation ◽  
Cycle Arrest ◽  
H460 Cell ◽  
H1975 Cell

Objective: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. Background: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. Methods: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. Results: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. Conclusion: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

The impact of Zataria multiflora Boiss extract on in vitro and in vivo Th1/Th2 cytokine (IFN-γ/IL4) balance

2013 ◽  
Vol 150 (3) ◽  
pp. 1024-1031 ◽  
Author(s):  
Mohammad Hossein Boskabady ◽  
Sakine Shahmohammadi Mehrjardi ◽  
Abadorrahim Rezaee ◽  
Houshang Rafatpanah ◽  
Sediqeh Jalali
Keyword(s):  
Zataria Multiflora ◽  
Th2 Cytokine ◽  
Ifn Γ ◽  
The Impact

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

Protective effect of argan oil on DNA damage in vivo and in vitro

Biomarkers ◽  
2021 ◽  
pp. 1-9
Author(s):  
Habiba Bouchab ◽  
Abbas Ishaq ◽  
Riad EL Kebbaj ◽  
Boubker Nasser ◽  
Gabriele Saretzki
Keyword(s):  
Dna Damage ◽  
Protective Effect ◽  
Argan Oil
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