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

Pieck, Anne Christin; Drescher, A.; Wiesmann, K G; Messerschmidt, J.; Weber, G.; Strumberg, Dirk; Hilger, Ralf A.; Scheulen, M. E.; Jaehde, Ulrich

doi:10.1038/sj.bjc.6604387

Cited by 24 publications

(22 citation statements)

References 40 publications

(48 reference statements)

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“…The observation that patients who did not receive the full protocol-specified oxaliplatin dose during CRT had favorable PFS is in line with reports (though from retrospective analyses), where neutropenia from oxaliplatin-containing chemotherapy was associated with improved survival in metastatic colorectal and gastric cancer [26, 27]. In this context, improved tumor response has been related to strong oxaliplatin-DNA adduct formation in white blood cells [28]. Additionally, in agreement with our findings, previous studies have reported low hemoglobin and circulating lymphocytes being adverse prognostic factors in LARC patients given neoadjuvant therapy [29, 30].…”

Section: Discussionsupporting

confidence: 82%

Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer

et al. 2016

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In colorectal cancer, immune effectors may be determinative for disease outcome. Following curatively intended combined-modality therapy in locally advanced rectal cancer metastatic disease still remains a dominant cause of failure. Here, we investigated whether circulating immune factors might correlate with outcome. An antibody array was applied to assay changes of approximately 500 proteins in serial serum samples collected from patients during oxaliplatin-containing induction chemotherapy and sequential chemoradiotherapy before final pelvic surgery. Array data was analyzed by the Significance Analysis of Microarrays software and indicated significant alterations in serum osteoprotegerin (TNFRSF11B) during the treatment course, which were confirmed by osteoprotegerin measures using a single-parameter immunoassay. Patients experiencing increase in circulating osteoprotegerin during the chemotherapy had significantly better 5-year progression-free survival than those without increase (78% versus 48%; P = 0.009 by log-rank test). Hence, systemic release of this soluble tumor necrosis factor decoy receptor following the induction phase of neoadjuvant therapy was associated with favorable long-term outcome in patients given curatively intended chemoradiotherapy and surgery but with metastatic disease as the main adverse event. This finding suggests that osteoprotegerin may mediate or reflect systemic anti-tumor immunity invoked by combined-modality therapy in locally advanced rectal cancer.

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Section: Discussionsupporting

confidence: 82%

Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer

et al. 2016

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“…investigated the effects of a dietary-relevant oral dose of 2-amino-1-methyl-6-phenylimidazo[4,5- b ]pyridine (PhIP) in a group of patients with colon cancer and showed an increase in PhIP-DNA adduct levels in peripheral blood DNA after exposure (19). The adduct levels reached a peak 2–4 h after exposure and decreased significantly over 24 h. Investigation of the kinetics of formation of DNA adducts after exposure to DNA binding compounds in humans has been mostly limited to studies testing clinical response to platinum-based therapies in cancer patients (20,21). …”

Section: Discussionmentioning

confidence: 99%

Kinetics of DNA Adduct Formation in the Oral Cavity after Drinking Alcohol

Balbo

Meng

Bliss

et al. 2012

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Alcohol consumption is one of the top-10 risks for the worldwide burden of disease and an established cause of head and neck cancer as well as cancer at other sites. Acetaldehyde, the major metabolite of ethanol, reacts with DNA to produce adducts, which are critical in the carcinogenic process and can serve as biomarkers of exposure and possibly of disease risk. Acetaldehyde associated with alcohol consumption is considered “carcinogenic to humans”. We have previously developed the technology to quantify acetaldehyde-DNA adducts in human tissues, but there are no studies in the literature defining the formation and removal of acetaldehyde-DNA adducts in people who consumed alcohol. Methods We investigated levels of N2-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at several time points after consumption of increasing alcohol doses. Ten healthy non-smokers were dosed once a week for three weeks. Mouthwash samples were collected before and at several time points after the dose. N2-Ethylidene-dGuo was measured as its NaBH3CN reduction product N2-ethyl-dGuo by LC-ESI-MS/MS. Results N2-ethylidene-dGuo levels increased as much as 100-fold from baseline within 4h after each dose for all subjects and in a dose responsive manner (p = 0.001). Conclusion These results demonstrate an effect of alcohol on oral cell DNA adduct formation, strongly supporting the key role of acetaldehyde in head and neck cancer caused by alcohol drinking. Impact Our results provide some of the first conclusive evidence linking exposure to a lifestyle carcinogen and kinetics of DNA adduct formation in humans.

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“…It also enters peripheral blood cells: dna adducts are present in leukocytes after oxaliplatin administration 20 . Whether this action contributes to hematologic toxicity is uncertain, but the number of platinum-dna adducts in the blood cells of patients treated with cisplatin correlates with the degree of leucopenia and thrombocytopenia 21 .…”

Section: The Hematopoietic Systemmentioning

confidence: 99%

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

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

Cited by 24 publications

References 40 publications

Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer

Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer

Kinetics of DNA Adduct Formation in the Oral Cavity after Drinking Alcohol

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

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