scholarly journals Increased DNA strand breaks in mononuclear cells from patients with rheumatoid arthritis.

1992 ◽  
Vol 51 (1) ◽  
pp. 8-12 ◽  
Author(s):  
L L Bhusate ◽  
K E Herbert ◽  
D L Scott ◽  
D Perrett
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Dna Strand

scholarly journals The Radioprotective Effect of Procaine and Procaine-Derived Product Gerovital H3 in Lymphocytes from Young and Aged Individuals

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Anca Ungurianu ◽  
Denisa Margina ◽  
Claudia Borsa ◽  
Cristina Ionescu ◽  
Gudrun von Scheven ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chemical Compounds ◽  
Dna Strand Breaks ◽  
Peripheral Blood Mononuclear ◽  
Strand Breaks ◽  
Young Subjects ◽  
Living Organisms ◽  
Dna Strand

Ionizing radiation induces genomic instability in living organisms, and several studies reported an ageing-dependent radiosensitivity. Chemical compounds, such as scavengers, radioprotectors, and modifiers, contribute to reducing the radiation-associated toxicity. These compounds are often antioxidants, and therefore, in order to be effective, they must be present before or during exposure to radiation. However, not all antioxidants provide radioprotection. In this study, we investigated the effects of procaine and of a procaine-based product Gerovital H3 (GH3) on the formation of endogenous and X-ray-induced DNA strand breaks in peripheral blood mononuclear cells (PBMCs) isolated from young and elderly individuals. Interestingly, GH3 showed the strongest radioprotective effects in PBMCs from young subjects, while procaine reduced the endogenous amount of DNA strand breaks more pronounced in aged individuals. Both procaine and GH3 inhibited lipid peroxidation, but procaine was more effective in inhibiting mitochondria free radicals’ generation, while GH3 showed a higher antioxidant action on macrophage-induced low-density lipoprotein oxidation. Our findings provide new insights into the mechanisms underlying the distinct effects of procaine and GH3 on DNA damage.

Positive Association Between DNA Strand Breaks in Peripheral Blood Mononuclear Cells and Polyunsaturated Fatty Acids in Red Blood Cells From Women

2007 ◽  
Vol 59 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Audur Y. Thorlaksdottir ◽  
Jon J. Jonsson ◽  
Laufey Tryggvadottir ◽  
Gudrun V. Skuladottir ◽  
Anna L. Petursdottir ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Peripheral Blood Mononuclear Cells ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Positive Association ◽  
Dna Strand Breaks ◽  
Peripheral Blood Mononuclear ◽  
Strand Breaks ◽  
Blood Mononuclear Cells ◽  
Dna Strand

Phase I study of TP300 in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2563-2563
Author(s):  
D. A. Anthoney ◽  
I. MacPherson ◽  
C. Twelves ◽  
D. Crawford ◽  
C. Siller ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Topoisomerase I ◽  
Mononuclear Cells ◽  
Dna Strand Breaks ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Strand Breaks ◽  
Starting Dose ◽  
Dna Strand

2563 Background: TP300 (CH4556300) is a synthetic camptothecin analogue and potent topoisomerase I inhibitor designed to have superior efficacy, tolerability and pharmacokinetic (PK) characteristics compared to current inhibitors. Intravenous (i/v) TP300 undergoes rapid chemical conversion to the active compound CH0793076, then enzymatic conversion to an active metabolite, CH0793011. The objectives of this study were to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and PK profiles of TP300; antitumor activity and pharmacodynamics (PD) were also evaluated. Methods: Eligible pts with refractory, advanced solid tumors who had adequate PS, hematologic, renal, and hepatic function were recruited into this open-label, modified- Fibonacci dose escalation (“3 + 3” pts/dose level, with expansion at the MTD) study. TP300 was given as a 1-hour i/v infusion 3-weekly; the starting dose was 1 mg/m2. The MTD was defined as the dose level below that where > 2 of 3–6 pts experienced DLT. PK profiles of TP300, CH0793076 and CH0793011 were analysed; DNA strand breaks in peripheral blood mononuclear cells (PBMCs) were measured with the comet assay as a PD marker. Results: 32 pts (m=20; f=12), median age 58 (range 31–72), received TP300 at doses of 1, 2, 4, 8, 12, then 10mg/m2. The MTD was 10mg/m2; DLTs seen at 12mg/m2 (2/4 pts) and 10mg/m2 (3/12 pts) included anaemia, thrombocytopenia and febrile neutropenia. Other grade 3/4 toxicities included lethargy, chills and lower back pain. Diarrhoea was uncommon. Seven pts, all previously treated with irinotecan, had disease stabilisation for 1.5–5 months. CH0793076 PK (AUC and Cmax) were linear from 1 to 10mg/m2. There was a strong PD relationship between CH0793076 AUC and fall in neutrophils, the threshold AUC for DLT neutropenia being 5 hr.umol/L. DNA strand breaks were detected consistently in PBMCs on completion of TP300 infusion . Conclusions: The Phase II starting dose will be 8mg/m2 because hematologic toxicity was seen in cycle 1 at the MTD. As the AUC of CH0793076 at MTD is substantially greater than that of SN38 in pts treated with irinotecan, and CH0793076 is almost equipotent to SN38 pre-clinically, a PK advantage for TP300 is confirmed. Further investigation is warranted. [Table: see text]

scholarly journals Repair of DNA Strand Breaks by the Overlapping Functions of Lesion-Specific and Non-Lesion-Specific DNA 3′ Phosphatases

2001 ◽  
Vol 21 (21) ◽  
pp. 7191-7198 ◽  
Author(s):  
John R. Vance ◽  
Thomas E. Wilson
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Synthetic Lethality ◽  
Dna Strand Breaks ◽  
Triple Mutant ◽  
Phosphatase Domain ◽  
Strand Breaks ◽  
Alternative Pathways ◽  
Processing Enzymes ◽  
Dna Strand

ABSTRACT In Saccharomyces cerevisiae, the apurinic/apyrimidinic (AP) endonucleases Apn1 and Apn2 act as alternative pathways for the removal of various 3′-terminal blocking lesions from DNA strand breaks and in the repair of abasic sites, which both result from oxidative DNA damage. Here we demonstrate that Tpp1, a homologue of the 3′ phosphatase domain of polynucleotide kinase, is a third member of this group of redundant 3′ processing enzymes. Unlike Apn1 and Apn2, Tpp1 is specific for the removal of 3′ phosphates at strand breaks and does not possess more general 3′ phosphodiesterase, exonuclease, or AP endonuclease activities. Deletion ofTPP1 in an apn1 apn2 mutant background dramatically increased the sensitivity of the double mutant to DNA damage caused by H2O2 and bleomycin but not to damage caused by methyl methanesulfonate. The triple mutant was also deficient in the repair of 3′ phosphate lesions left by Tdp1-mediated cleavage of camptothecin-stabilized Top1-DNA covalent complexes. Finally, the tpp1 apn1 apn2 triple mutation displayed synthetic lethality in combination with rad52, possibly implicating postreplication repair in the removal of unrepaired 3′-terminal lesions resulting from endogenous damage. Taken together, these results demonstrate a clear role for the lesion-specific enzyme, Tpp1, in the repair of a subset of DNA strand breaks.

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