Toxicity, Clastogenicity and Genotoxicity of Theophylline and Pentoxifylline in Mammalian Cells Cultured In Vitro

— As part of a developmental study on theophylline and pentoxifylline, these drugs were tested for possible cytotoxic, mutagenic and clastogenic effects on V79 hamster cells and human lymphocytes cultured in vitro. After the short-term treatment of V79 cells with theophylline and pentoxifylline, the cells were relatively resistant to the toxic effects of these methylxanthines. Generally, only high concentrations of theophylline or pentoxifylline had toxic effects on exposed V79 cells. Short-term treatment of V79 cells with theophylline or pentoxifylline did not induce 6-thioguanine resistant mutations in either the presence or absence of S9 fractions. However, in the absence of an S9 fraction, elevated levels of single-strand breaks in DNA were induced. Both methylxanthines caused clastogenic effects in human lymphocytes and hamster V79 cells after long-term exposure. We suggest that theophylline and pentoxifylline are clastogenic but not genotoxic, and that the molecular mechanism for the induction of single-strand breaks in DNA and the induction of chromosomal aberrations in cells treated with theophylline and pentoxifylline is not the induction of lesions in the DNA but the inhibition of DNA chain elongation.

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Single-strand breaks or alkali-sensitive sites in the DNA of human myeloma plasma cells and chronic lymphocytic leukemia lymphocytes

Canadian Journal of Biochemistry and Cell Biology ◽

10.1139/o85-120 ◽

1985 ◽

Vol 63 (9) ◽

pp. 977-981 ◽

Cited By ~ 3

Author(s):

L. Brox ◽

A. Ng ◽

E. Pollock ◽

A. Khaliq ◽

A. Belch

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Plasma Cells ◽

Human Lymphocytes ◽

Single Strand ◽

Lymphocytic Leukemia ◽

General Mechanism ◽

Alkaline Elution ◽

Strand Breaks ◽

Single Strand Breaks

Alkaline-elution studies showed significant levels of either DNA single-strand breaks or alkali-sensitive sites in the plasma cells of six out of six myeloma patients and in the lymphocytes of two out of four patients with chronic lymphocytic leukemia as compared with normal human lymphocytes. The increased rate of DNA elution was variable from sample to sample with a range that would correspond to that observed with 100–1000 rad (1 rad = 10 mGy) of X-ray irradiation. This alteration in DNA structure was observed in both new and advanced patients, did not appear to be related to prior therapy, and did not affect the in vitro viability of these cells. Repetitive alkaline-elution profiles obtained with tumor cells from three patients were similar on subsequent samples obtained 1 month apart. Altered DNA elution was not evident in peripheral blood lymphocytes from myeloma patients with altered plasma cell DNA elution. These observations are interesting in light of the recent hypothesis that breaking and rejoining of DNA, regulated by poly(ADP-ribosyl)ation, may be a general mechanism of altering gene expression during differentiation.

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In vitro effects of methadone on lymphocyte proliferation following a short-term treatment with methotrexate-loaded liposomes in a murine model of arthritis

Toxicology Letters ◽

10.1016/j.toxlet.2006.06.233 ◽

2006 ◽

Vol 164 ◽

pp. S110-S111

Author(s):

Maria Barca ◽

Anne Marie Ciobanu ◽

Dan Balalau ◽

Daniela Luiza Baconi ◽

Mihaela Ilie ◽

...

Keyword(s):

Murine Model ◽

Lymphocyte Proliferation ◽

Term Treatment ◽

Short Term ◽

Short Term Treatment ◽

In Vitro Effects

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Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy

The Journal of Comparative Neurology ◽

10.1002/cne.1087 ◽

2001 ◽

Vol 432 (1) ◽

pp. 35-60 ◽

Cited By ~ 41

Author(s):

Zhiping Liu ◽

Lee J. Martin

Keyword(s):

Nitric Oxide ◽

Motor Neurons ◽

Single Strand ◽

Strand Breaks ◽

Single Strand Breaks ◽

In Vitro Exposure

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Evaluation of cytotoxicity and mutagenicity of the benzodiazepine flunitrazepam in vitro and in vivo

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502014000200003 ◽

2014 ◽

Vol 50 (2) ◽

pp. 251-256

Author(s):

Igor Vivian de Almeida ◽

Giovana Domingues ◽

Lilian Capelari Soares ◽

Elisângela Düsman ◽

Veronica Elisa Pimenta Vicentini

Keyword(s):

Rattus Norvegicus ◽

Bone Marrow Cells ◽

Micronucleus Test ◽

Term Treatment ◽

Genotoxic Effects ◽

Short Term ◽

Short Term Treatment ◽

Chromosomal Aberration Test

Flunitrazepam (FNZ) is a sedative benzodiazepine prescribed for the short-term treatment of insomnia. However, there are concerns regarding possible carcinogenic or genotoxic effects of this medicine. Thus, the aim of this study was to evaluate the cytotoxic, clastogenic and aneugenic effects of FNZ in hepatoma cells from Rattus norvegicus (HTC) in vitro and in bone marrow cells of Wistar rats in vivo. These effects were examined in vitro following treatment with 0.2, 1.0, 5.0 or 10 μg/mL FNZ using a micronucleus test with a cytokinesis block or in vivo using a chromosomal aberration test following treatment with 7, 15 or 30 μg/mL/kg body weight. The results showed that the benzodiazepine concentrations tested were not cytotoxic, aneugenic or clastogenic. However, considering the adverse effects of using this benzodiazepine, more studies are required.

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Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02680-20 ◽

2021 ◽

Author(s):

Karen A. Gammeltoft ◽

Yuyong Zhou ◽

Carlos R. Duarte Hernandez ◽

Andrea Galli ◽

Anna Offersgaard ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitors ◽

Viral Suppression ◽

Term Treatment ◽

Short Term ◽

Short Term Treatment ◽

Direct Acting Antiviral ◽

Human Lung Carcinoma

Antivirals targeting SARS-CoV-2 could improve treatment of COVID-19. We evaluated efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PI) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PI showed differential potency in short-term treatment assays based on detection of SARS-CoV-2 Spike protein in VeroE6 cells. Linear PI boceprevir, telaprevir and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among macrocyclic PI, simeprevir had the highest (EC50 15 μM) and glecaprevir the lowest (EC50 >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir and deldeprevir in between. Acyclic PI asunaprevir and faldaprevir had EC50 of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had EC50 of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PI. In short-term treatments, combination of macrocyclic but not linear PI with remdesivir showed synergism in VeroE6 and A549-hACE2 cells. Longer-term treatment of infected VeroE6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform development and application of protease inhibitors for optimized antiviral treatments of COVID-19.

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