Platinum drug-DNA interactions in human tissues measured by cisplatin-DNA enzyme-linked immunosorbent assay and atomic absorbance spectroscopy.

Poirier, Miriam C.; Reed, Eddie; Shamkhani, Hanadi; Tarone, Robert E.; Gupta-Burt, Shalina

doi:10.1289/ehp.9399149

Cited by 28 publications

(16 citation statements)

References 11 publications

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“…16–18, 40–44 Radiocarbon content in the DNA was measured by AMS according to published protocols. 27 The levels of carboplatin-DNA monoadducts were readily detectable and ranged from 0.23 to 1.30 monoadducts per 10 8 nucleotides (Figure 6B and SI table 2).…”

Section: Resultsmentioning

confidence: 99%

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

et al. 2017

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The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts—the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [14C]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R2=0.95, p<0.0001) and correlated with IC50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p=0.02 and p=0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK), and [14C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [14C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14C]carboplatin formulation for the microdose was 107 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response.

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Section: Resultsmentioning

confidence: 99%

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

et al. 2017

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“…In cancer patients treated with Pt drugs, positive correlations between levels of Pt-induced DNA adducts in peripheral blood mononuclear cells, as surrogates for tumor tissue, and good clinical outcomes are reported, 6–13 but with some inconsistencies. 14–16 The insufficiently sensitive methods used in these studies required patients to receive toxic full doses of chemotherapy before DNA damage and chemoresistance could be assessed—a considerable disadvantage for clinical applications.…”

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confidence: 99%

A microdosing approach for characterizing formation and repair of carboplatin–DNA monoadducts and chemoresistance

Henderson

et al. 2011

Intl Journal of Cancer

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Formation and repair of platinum (Pt)-induced DNA adducts is a critical step in Pt drug-mediated cytotoxicity. Measurement of Pt–DNA adduct kinetics in tumors may be useful for better understanding chemoresistance and therapeutic response. However, this concept has yet to be rigorously tested because of technical challenges in measuring the adducts at low concentrations and consistent access to sufficient tumor biopsy material. Ultrasensitive accelerator mass spectrometry was used to detect [14C]carboplatin–DNA monoadducts at the attomole level, which are the precursors to Pt–DNA crosslink formation, in six cancer cell lines as a proof-of-concept. The most resistant cells had the lowest monoadduct levels at all time points over 24 hr. [14C]Carboplatin “microdoses" (1/100th the pharmacologically effective concentration) had nearly identical adduct formation and repair kinetics compared to therapeutically relevant doses, suggesting that the microdosing approach can potentially be used to determine the pharmacological effects of therapeutic treatment. Some of the possible chemoresistance mechanisms were also studied, such as drug uptake/efflux, intracellular inactivation and DNA repair in selected cell lines. Intracellular inactivation and efficient DNA repair each contributed significantly to the suppression of DNA monoadduct formation in the most resistant cell line compared to the most sensitive cell line studied (p < 0.001). Nucleotide excision repair (NER)-deficient and - proficient cells showed substantial differences in carboplatin monoadduct concentrations over 24 hr that likely contributed to chemoresistance. The data support the utility of carboplatin microdosing as a translatable approach for defining carboplatin–DNA monoadduct formation and repair, possibly by NER, which may be useful for characterizing chemoresistance in vivo.

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“…42,46,47,80−87 For example, in a series of ELISA-based clinical studies of ovarian and testicular cancer patients conducted by Reed et al, 44,45,48,81 significantly higher platinum-DNA adduct levels were observed in isolated leukocyte DNA after cisplatin- or carboplatin-based chemotherapy in patients with good clinical outcome. They further expanded the patient population to include breast, lung, colon, and squamous sarcoma cancer patients, by analyzing platinum levels in leucocyte DNA via AAS.…”

Section: Platinum Drugs and Combination Therapiesmentioning

confidence: 99%

“…They further expanded the patient population to include breast, lung, colon, and squamous sarcoma cancer patients, by analyzing platinum levels in leucocyte DNA via AAS. 49,80 More recently, Pieck et al investigated the formation of oxaliplatin-DNA adducts in WBCs isolated from patients with various malignancies. 86 The use of the more sensitive adsorptive stripping voltammetry enabled the quantitation of the generally lower oxaliplatin-DNA adduct level after administration of systemic oxaliplatin based chemotherapy.…”

Section: Platinum Drugs and Combination Therapiesmentioning

confidence: 99%

“…47,80 Low DNA adduct levels measured by ELISA consistently correlated with disease progression, whereas in some initial AAS-based studies, the incorporation of total platinum failed to show such a correlation. 64,88,89 Adduct level measurements via ELISA and AAS by Motzer et al, or via ICP-MS by Bonetti et al, showed no differences between responsive and nonresponsive patient populations.…”

Section: Platinum Drugs and Combination Therapiesmentioning

confidence: 99%

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DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine

Stornetta

Zimmermann

Cimino

et al. 2017

Chem. Res. Toxicol.

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Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge.

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Platinum drug-DNA interactions in human tissues measured by cisplatin-DNA enzyme-linked immunosorbent assay and atomic absorbance spectroscopy.

Cited by 28 publications

References 11 publications

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

A microdosing approach for characterizing formation and repair of carboplatin–DNA monoadducts and chemoresistance

DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine

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