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

Stornetta, Alessia; Zimmermann, Maike; Cimino, George D.; Henderson, Paul; Sturla, Shana J.

doi:10.1021/acs.chemrestox.6b00380

Cited by 48 publications

(73 citation statements)

References 156 publications

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“…The efficacy of Pt-based drugs for cancer treatment relates to the formation of Pt-DNA adducts resulting in DNA damage, which hinder mitotic processes and halt cell division. Drawbacks of the formation of Pt-DNA adducts include the high rate of DNA damage in non-target cells or healthy tissue 36 . We determined the extent of Pt-DNA adduct formation by extracting genomic DNA from different tissues and quantifying the amount of Pt using high-resolution ICP-MS. Figure 1D shows the relative Pt uptake within specific tissues leading to Pt-DNA adduct formation 24 h after injection.…”

Section: Resultsmentioning

confidence: 99%

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Nadar

Farbod

Schilden

et al. 2020

Sci Rep

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platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195m Pt-BP) complexes to confirm preferential accumulation of these pt-based drugs in metabolically active bone. In vitro nMR studies revealed that release of pt from pt Bp complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. these pt-Bp complexes formed less pt-DnA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of pt from pt-Bp complexes proceeded relatively slow. Subsequently, radioactive 195m pt-Bp complexes were synthesized using 195m pt(no 3) 2 (en) as precursor and injected intravenously into mice. Specific accumulation of 195m pt-Bp was observed at skeletal sites with high metabolic activity using micro-Spect/ct imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195m pt Bp colocalized with calcium in the trabeculae of mice tibia. Most types of tumors, i.e. breast, prostate, lung, kidney, and thyroid, metastasize to bone since its physiological environment facilitates the formation and growth of cancer cells 1,2. These metastases affect healthy bone, which then become the primary cause of mortality 3. Distant metastases are the leading cause of death for both breast and prostate cancer patients, with 65-75% and 90% of these patients developing bone metastases in advanced stages, respectively 4,5. Bone metastases are often associated with accelerated bone resorption leading to complications such as skeletal-related events (SREs), bone pain or hypercalcemia 6,7. Unfortunately, current treatments for bone metastases are limited. Bisphosphonates (BP) and denosumab are most commonly used for palliative treatment to prevent or limit SREs 8. Although such treatments inhibit osteoclast activity and prevent the progression of metastases, they do not kill cancer cells effectively and do not improve the quality of life of patients substantially 9. Consequently, the development of effective therapies to treat bone metastases remains a major clinical challenge.

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Section: Resultsmentioning

confidence: 99%

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Nadar

Farbod

Schilden

et al. 2020

Sci Rep

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“…It can be envisioned that O 6 -MeG induced by methylating anticancer drugs such as TMZ and DTIC could be monitored in peripheral blood cells as clinical pharmacodynamic biomarker in the future, comparable to γH2AX and poly(ADP-ribose) as proposed elsewhere (Redon et al 2010). This will assist in stratifying patients and monitoring therapeutic efficacy in personalized medicine, an approach that is also amenable to other DNA damaging anticancer drugs, including cis-platin and cyclophosphamide (Stornetta et al 2017). The advantages and disadvantages of each method used here are summarized in Table 3. Very recently, novel strategies have been developed to detect O 6 -MeG in a sequencespecific context.…”

Section: Discussionmentioning

confidence: 99%

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo

et al. 2018

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N-nitroso compounds are alkylating agents, which occur widespread in diet and environment. They induce DNA alkylation adducts such as O 6-methylguanine (O 6-MeG), which is repaired by O 6-methylguanine-DNA methyltransferase (MGMT). Persistent O 6-MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O 6-MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) to monitor O 6-MeG adducts. First, colorectal cancer (CRC) cells were treated with the methylating anticancer drug temozolomide (TMZ). Immunofluorescence microscopy and an immuno-slot blot assay, both based on an adductspecific antibody, allowed for the semi-quantitative, dose-dependent assessment of O 6-MeG in CRC cells. Using the highly sensitive and specific UPLC-MS/MS, TMZ-induced O 6-MeG adducts were quantified in CRC cells and even in peripheral blood mononuclear cells exposed to clinically relevant TMZ doses. Furthermore, all methodologies were used to detect O 6-MeG in wildtype (WT) and MGMT-deficient mice challenged with the carcinogen azoxymethane. UPLC-MS/MS measurements and dose-response modeling revealed a nonlinear formation of hepatic and colonic O 6-MeG adducts in WT, whereas linear O 6-MeG formation without a threshold was observed in MGMT-deficient mice. Collectively, the UPLC-MS/MS analysis is highly sensitive and specific for O 6-MeG, thereby allowing for the first time for the determination of thresholds upon exposure to O 6-methylating agents. We envision that this method will be instrumental to monitor the efficacy of methylating chemotherapy and to assess dietary exposures. MATERIAL AND METHODS Material All solutions were made with deionized water (18.2 MΩ resistivity). O 6-methyl-d3-guanine (O 6-Me-d3-G) was from Toronto Research Chemicals (Toronto, Canada). O 6-MeG, ammonium hydroxide (ACS Reagent 28-30 %), hydrochloric acid (ACS Reagent 37 %), and acetic acid (HPLC grade) were purchased from Sigma-Aldrich (Buchs, Switzerland). Guanine was obtained from Acros Organics (New Jersey, USA) and Strata-X polymeric columns (30 μm) were from Phenomenex (Torrance, USA). Methanol (HPLC Gradient Grade) was bought at VWR (Dietikon, Switzerland).

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“…Alternatively, the DNA adducts can be quantified by the SILAM-SRM approach in peripheral blood mononuclear cells or tumor biopsy isolated from patients treated with a microdose of the DNA alkylating drug, whereas another potential scenario for sensitivity testing might involve ex vivo exposure of cancerous or normal surrogate cells to the DNA alkylating drug with evaluation of adduct formation. 27 …”

Section: Discussionmentioning

confidence: 99%

DNA Adduct Profiles Predict in Vitro Cell Viability after Treatment with the Experimental Anticancer Prodrug PR104A

Stornetta

Villalta

Gossner

et al. 2017

Chem. Res. Toxicol.

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PR104A is an experimental DNA-alkylating hypoxia-activated prodrug that can also be activated in an oxygen-independent manner by the two-electron aldo-keto reductase 1C3. Nitroreduction leads to the formation of cytotoxic hydroxylamine (PR104H) and amine (PR104M) metabolites, which induce DNA mono and cross-linked adducts in cells. PR104A-derived DNA adducts can be utilized as drug-specific biomarkers of efficacy and as a mechanistic tool to elucidate the cellular and molecular effects of PR104A. Toward this goal, a mass spectrometric bioanalysis approach based on a stable isotope-labeled adduct mixture (SILAM) and selected reaction monitoring (SRM) data acquisition for relative quantitation of PR104A-derived DNA adducts in cells was developed. Use of this SILAM-based approach supported simultaneous relative quantitation of 33 PR104A-derived DNA adducts in the same sample, which allowed testing of the hypothesis that the enhanced cytotoxicity, observed by preconditioning cells with the transcription-activating isothiocyanate sulforaphane, is induced by an increased level of DNA adducts induced by PR104H and PR104M, but not PR104A. By applying the new SILAM-SRM approach, we found a 2.4-fold increase in the level of DNA adducts induced by PR104H and PR104M in HT-29 cells preconditioned with sulforaphane and a corresponding 2.6-fold increase in cytotoxicity. These results suggest that DNA adduct levels correlate with drug potency and underly the possibility of monitoring PR104A-derived DNA adducts as biomarkers of efficacy.

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

Cited by 48 publications

References 156 publications

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo

DNA Adduct Profiles Predict in Vitro Cell Viability after Treatment with the Experimental Anticancer Prodrug PR104A

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