DNA damage and repair in peripheral blood lymphocytes from healthy individuals and cancer patients: A pilot study on the implications in the clinical response to chemotherapy

Nadin, Silvina B.; Vargas–Roig, Laura M.; Drago, Gisela; Ibarra, Jorge E.; Ciocca, Daniel R.

doi:10.1016/j.canlet.2005.07.025

Cited by 62 publications

(68 citation statements)

References 42 publications

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“…However, the poor accessibility of tumour tissue is a major obstacle for routine measurement. Therefore, white blood cells (WBC) have been considered as surrogate cells (Reed et al, 1988;Poirier et al, 1992;Nadin et al, 2006). Various clinical studies with cisplatin have shown that tumour response is related to platinum-DNA adduct levels in WBC Parker et al, 1991;Schellens et al, 1996).…”

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confidence: 99%

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

et al. 2008

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In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m À2 oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials.

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confidence: 99%

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

et al. 2008

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“…Several groups have also detected diverse damaging effects of cisplatin over DNA, like adduction, fragmentation and crosslinking (Ferrer et al 2003;Goodisman et al 2006;Nadin et al 2006) DNA was damaged in most of the cells exposed, so the cisplatin dose was high enough to be a meaningful challenge to murine PBL genetic material. Therefore, any significant reduction in the proportion of damaged cells, or a shift to lower levels in DNA migration, should be attributed to amifostine protective effect.…”

Section: Discussionmentioning

confidence: 99%

Amifostine (WR2721) Confers DNA Protection to in Vivo Cisplatin-Treated Murine Peripheral Blood Leukocytes

2009

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ᮀ Amifostine [S-2-3-aminopropil amino ethyl phosphorotioic acid], a modulator agent for antineoplastic drugs involved in free radicals generation has given controversial results in cisplatin treated leukocytes in vitro. We have evaluated the amifostine protection over leukocytes in vivo, using comet assay. Groups of five OF1 male mice were given one of three doses of amifostine (56, 105 and 200 mg/Kg) after a cisplatin single injection (10 mg/Kg). Serum malonyldialdehide levels, catalase and superoxide dismutase activity were also evaluated. Amifostine showed significant DNA protection (p< 0.01) at the two lower doses evaluated. Malonyldildehide decreased in all amifostine treatments with respect to cisplatin while antioxidant enzyme activities remained unchanged. However, DNA migration increased with the highest amifostine dose; in fact highest dose of amifostine did no protect damage caused by cisplatin this result have implications on amifostine treatment schedules in clinical practice.

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“…In 2006, Nadin et al (2006) reported a decrease in hMLH1 protein expression in the lymphocytes of cancer patients after polychemotherapy. In fact, previously published data showed that Adriamycin (a crosslinking agent) reversibly inhibited human mismatch repair in vitro at low micromolar concentrations by interacting with the MMR pathway through a mechanism distinct from the manner by which covalent DNA lesions are processed.…”

Section: Discussionmentioning

confidence: 99%

No Relationship between the Amount of DNA Damage and the Level of hMLH1 and RASSF1A Gene Expression in Bladder Cancer Cells Treated with Cisplatin and Gemcitabine

Camargo

Silva²,

Gobette³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Tumor response to antineoplastic drugs is not always predictable. This is also true for bladder carcinoma, a highly recurrent neoplasia. Currently, the combination of cisplatin and gemcitabine is well accepted as a standard protocol for treating bladder carcinoma. However, in some cases, this treatment protocol causes harmful side effects. Therefore, we investigated the roles of the genes TP53, RASSF1A (a tumor suppressor gene) and hMLH1 (a gene involved in the mismatch repair pathway) in cell susceptibility to cisplatin/gemcitabine treatment. Two bladder transitional carcinoma cell (TCC) lines, RT4 (wild-type TP53) and 5637 (mutated TP53), were used in this study. First, we evaluated whether the genotoxic potential of cisplatin/gemcitabine was dependent on TP53 status. Then, we evaluated whether the two antineoplastic drugs modulated RASSF1A and hMLH1 expression in the two cell lines. Increased DNA damage was observed in both cell lines after treatment with cisplatin or gemcitabine and with the two drugs simultaneously, as depicted by the comet assay. A lack of RASSF1A expression and hypermethylation of its promoter were observed before and after treatment in both cell lines. On the other hand, hMLH1 downregulation, unrelated to methylation status, was observed in RT4 cells after treatment with cisplatin or with cisplatin and gemcitabine simultaneously (wild-type TP53); in 5637 cells, hMLH1 was upregulated only after treatment with gemcitabine. In conclusion, the three treatment protocols were genotoxic, independent of TP53 status. However, cisplatin was the most effective, causing the highest level of DNA damage in both wild-type and mutated TP53 cells. Gemcitabine was the least genotoxic agent in both cell lines. Furthermore, no relationship was observed between the amount of DNA damage and the level of hMLH1 and RASSF1A expression. Therefore, other alternative pathways might be involved in cisplatin and gemcitabine genotoxicity in these two bladder cancer cell lines.

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DNA damage and repair in peripheral blood lymphocytes from healthy individuals and cancer patients: A pilot study on the implications in the clinical response to chemotherapy

Cited by 62 publications

References 42 publications

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

Amifostine (WR2721) Confers DNA Protection to in Vivo Cisplatin-Treated Murine Peripheral Blood Leukocytes

No Relationship between the Amount of DNA Damage and the Level of hMLH1 and RASSF1A Gene Expression in Bladder Cancer Cells Treated with Cisplatin and Gemcitabine

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