Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure

Abstract Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S- adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.

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Enhancement in repair of radiation-induced DNA strand breaks in vivo by tocopherol monoglucoside

International Journal of Low Radiation ◽

10.1504/ijlr.2007.014488 ◽

2007 ◽

Vol 4 (1) ◽

pp. 43 ◽

Cited By ~ 2

Author(s):

Veena Prakash Salvi ◽

Dharmendra Kumar Maurya ◽

Tsutomu V. Kagiya ◽

Cherupally Krishnan Krishnan Nair

Keyword(s):

Dna Strand Breaks ◽

Strand Breaks ◽

Radiation Induced ◽

Dna Strand

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Prevention of base excision repair by TRC102 (methoxyamine) potentiates the anti-tumor activity of pemetrexed in vitro and in vivo

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.13005 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 13005-13005 ◽

Cited By ~ 2

Author(s):

L. Liu ◽

A. Bulgar ◽

J. Donze ◽

B. J. Adams ◽

C. P. Theuer ◽

...

Keyword(s):

Excision Repair ◽

Alkylating Agents ◽

Phase 1 ◽

Dna Strand Breaks ◽

Strand Breaks ◽

Ap Sites ◽

Dna Strand ◽

Anti Tumor Activity

13005 Background: TRC102 (methoxyamine) reverses resistance to alkylating agents by inhibiting base excision repair (BER; a mechanism of DNA repair), thereby increasing DNA strand breaks and potentiating the anti-tumor activity of alkylating agents without additional toxicity, Based on these data, TRC102 is currently being studied in combination with temozolomide in a phase 1 trial. We hypothesized that inhibition of BER by TRC102 would also increase DNA strand breaks and improve the anti-tumor activity of anti-metabolite chemotherapeutics, including pemetrexed, because these agents also produce AP sites that are recognized and repaired by BER. Methods: Pemetrexed- induced AP sites and BER inhibition was quantified using an apurinic/apyrimidinic (AP) site assay in vitro. Single and double DNA strand breaks were quantified by the Comet assay in vitro and anti-tumor activity was assessed in an in vivo xenograft study of subcutaneously implanted H460 human lung cancer cells. Results: Pemetrexed induced and TRC102 reduced the number of available AP sites in pemetrexed- treated H460 cells (by 60–80%), indicating successful inhibition of BER. TRC102 treatment increased DNA strand breaks in pemetrexed-treated H460 cells (2 fold increase versus treatment with pemetrexed alone). Premetrexed treatment alone and in combination with TRC 102 delayed tumor growth in vivo (tumor growth delay of 4.7 days in the 150 mg/m2 pemetrexed alone group, 5.7 days in the 150 mg/m2 pemetrexed + 2 mg/m2 TRC102 group and 6.9 days in the 150 mg/m2 pemetrexed + 4 mg/m2 TRC102 group); in vivo systemic toxicity was not increased. TRC102 alone had no effect in vitro or in vivo. Conclusions: TRC102 effectively inhibits BER in lung cancer cells treated with pemetrexed. Inhibition of DNA repair by TRC102 results in an increase in DNA strand breaks and improved anti-tumor activity versus treatment with pemetrexed alone. Given its preclinical efficacy and safety profile, study of TRC102 combined with pemetrexed in a phase 1 trial is warranted. No significant financial relationships to disclose.

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Dual labeling of the cytoskeleton and DNA strand breaks in porcine embryos produced in vivo and in vitro

Molecular Reproduction and Development ◽

10.1002/(sici)1098-2795(199809)51:1<59::aid-mrd7>3.0.co;2-v ◽

1998 ◽

Vol 51 (1) ◽

pp. 59-65 ◽

Cited By ~ 37

Author(s):

Charles R. Long ◽

John R. Dobrinsky ◽

Wesley M. Garrett ◽

Lawrence A. Johnson

Keyword(s):

Dna Strand Breaks ◽

Strand Breaks ◽

Dna Strand

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Induction of CAF-1 Expression in Response to DNA Strand Breaks in Quiescent Human Cells

Molecular and Cellular Biology ◽

10.1128/mcb.26.5.1839-1849.2006 ◽

2006 ◽

Vol 26 (5) ◽

pp. 1839-1849 ◽

Cited By ~ 30

Author(s):

Arman Nabatiyan ◽

Dávid Szüts ◽

Torsten Krude

Keyword(s):

Excision Repair ◽

Dna Strand Breaks ◽

Significant Loss ◽

Human Cells ◽

Dna Breaks ◽

Strand Breaks ◽

Quiescent Cells ◽

Dna Strand

ABSTRACT Genome stability in eukaryotic cells is maintained through efficient DNA damage repair pathways, which have to access and utilize chromatin as their natural template. Here we investigate the role of chromatin assembly factor 1 (CAF-1) and its interacting protein, PCNA, in the response of quiescent human cells to DNA double-strand breaks (DSBs). The expression of CAF-1 and PCNA is dramatically induced in quiescent cells upon the generation of DSBs by the radiomimetic drug bleocin (a bleomycin compound) or by ionizing radiation. This induction depends on DNA-PK. CAF-1 and PCNA are recruited to damaged chromatin undergoing DNA repair of single- and double-strand DNA breaks by the base excision repair and nonhomologous end-joining pathways, respectively, in the absence of extensive DNA synthesis. CAF-1 prepared from repair-proficient quiescent cells after induction by bleocin mediates nucleosome assembly in vitro. Depletion of CAF-1 by RNA interference in bleocin-treated quiescent cells in vivo results in a significant loss of cell viability and an accumulation of DSBs. These results support a novel and essential role for CAF-1 in the response of quiescent human cells to DSBs, possibly by reassembling chromatin following repair of DNA strand breaks.

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