Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients.

Han, Catherine; Khwaounjoo, Prashannata; Kilfoyle, Dean; Hill, Andrew; McKeage, Mark J.

doi:10.1200/jco.2014.32.3_suppl.578

Cited by 3 publications

(3 citation statements)

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“…), these in vitro treatments equated to AUCs for oxaliplatin exposure of 21.7, 65 and 217 μM.h, respectively, or to those achieved after 1.5, 4.3 and 14 standard clinical doses of oxaliplatin chemotherapy (85–130 mg/m 2 ) respectively (Han et al . ). Representative images suggested the presence of reductions in neuronal EU labelling fluorescence intensity and in cell body size after oxaliplatin treatment (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…Cultured DRG cells were treated with oxaliplatin and other platinum drugs using in vitro experimental conditions mimicking clinically achievable chemotherapy drug systemic exposures (Han et al . ). Effects of in vitro treatment with platinum drugs on DRG neuronal size and global transcriptional activity were related to levels of platinum DNA binding, measured by inductively coupled plasma mass spectrometry (Brouwers et al .…”

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confidence: 97%

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Role of platinum DNA damage‐induced transcriptional inhibition in chemotherapy‐induced neuronal atrophy and peripheral neurotoxicity

Yan

Liu

et al. 2015

Journal of Neurochemistry

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Platinum-based anticancer drugs cause peripheral neurotoxicity by damaging sensory neurons within the dorsal root ganglia (DRG), but the mechanisms are incompletely understood. The roles of platinum DNA binding, transcription inhibition and altered cell size were investigated in primary cultures of rat DRG cells. Click chemistry quantitative fluorescence imaging of RNAincorporated 5-ethynyluridine showed high, but wide ranging, global levels of transcription in individual neurons that correlated with their cell body size. Treatment with platinum drugs reduced neuronal transcription and cell body size to an extent that corresponded to the amount of preceding platinum DNA binding, but without any loss of neuronal cells. The effects of platinum drugs on neuronal transcription and cell body size were inhibited by blocking platinum DNA binding with sodium thiosulfate, and mimicked by treatment with a model transcriptional inhibitor, actinomycin D. In vivo oxaliplatin treatment depleted the total RNA content of DRG tissue concurrently with altering DRG neuronal size. These findings point to a mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. DRG neurons may be particularly vulnerable to this mechanism of toxicity because of their requirements for high basal levels of global transcriptional activity. Keywords: anticancer drug toxicity, DNA damage, DRG neurons, global transcription, neuronal atrophy, neurotoxicity. The platinum-based anticancer drugs, cisplatin, carboplatin and oxaliplatin, are used clinically for the routine treatment of a wide range of human cancers. Their mechanism of action involves platinum binding to DNA at the N7 position of purine bases to form bifunctional 1,2-and 1,3-intrastrand crosslinks on the DNA template, which inhibit DNA replication and transcription, leading to tumour cell cycle arrest and apoptosis (Wang and Lippard 2005). Platinum drugs also cause peripheral neurotoxicity by damaging postmitotic dorsal root ganglia (DRG) sensory neurons (Avan et al. 2015). In the clinic, the resulting neurological symptoms and functional deficits can interfere with the delivery of cancer chemotherapy or persist long after completion of treatment, thereby compromising patient quality of life and the chance of cancer control or cure. Abbreviations used: AUC, area under the concentration-time curve; DACH, diaminocyclohexane; DNA-PK, DNA-dependent protein kinase; DRG, dorsal root ganglia; EU, 5-ethynyluridine; IQR, interquartile range; PARP-1, poly(ADP-ribose) polymerase 1; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling.

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Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 97%

Role of platinum DNA damage‐induced transcriptional inhibition in chemotherapy‐induced neuronal atrophy and peripheral neurotoxicity

Yan

Liu

et al. 2015

Journal of Neurochemistry

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“…Although various preventive measures are adopted in clinic, the serious toxicities still occur. For instance, calcium and magnesium (Ca/Mg) infusions were recommended as an effective method to reduce oxaliplatin‐induced neurotoxicity, but recent phase I and II studies demonstrated that Ca/Mg infusions did not seem to prevent acute neurotoxicity of oxaliplatin . In addition, the biotransformation in the bloodstream also contributes to the side effects of platinum (II) complex .…”

Section: Challenges Of Platinum (Ii) Complex Drugsmentioning

confidence: 99%

Recent Advances in Platinum (IV) Complex‐Based Delivery Systems to Improve Platinum (II) Anticancer Therapy

Han

Sun

Wang

et al. 2015

Medicinal Research Reviews

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Cisplatin and its platinum (Pt) (II) derivatives play a key role in the fight against various human cancers such as testicular, ovarian, head and neck, lung tumors. However, their application in clinic is limited due to dose- dependent toxicities and acquired drug resistances, which have prompted extensive research effort toward the development of more effective Pt (II) delivery strategies. The synthesis of Pt (IV) complex is one such an area of intense research fields, which involves their in vivo conversion into active Pt (II) molecules under the reducing intracellular environment, and has demonstrated encouraging preclinical and clinical outcomes. Compared with Pt (II) complexes, Pt (IV) complexes not only exhibit an increased stability and reduced side effects, but also facilitate the intravenous-to-oral switch in cancer chemotherapy. The overview briefly analyzes statuses of Pt (II) complex that are in clinical use, and then focuses on the development of Pt (IV) complexes. Finally, recent advances in Pt (IV) complexes in combination with nanocarriers are highlighted, addressing the shortcomings of Pt (IV) complexes, such as their instability in blood and irreversibly binding to plasma proteins and nonspecific distribution, and taking advantage of passive and active targeting effect to improve Pt (II) anticancer therapy.

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Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain

et al. 2017

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Phase I drug-interaction study of effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and acute neurotoxicity in colorectal cancer patients.

Cited by 3 publications

References 20 publications

Role of platinum DNA damage‐induced transcriptional inhibition in chemotherapy‐induced neuronal atrophy and peripheral neurotoxicity

Role of platinum DNA damage‐induced transcriptional inhibition in chemotherapy‐induced neuronal atrophy and peripheral neurotoxicity

Recent Advances in Platinum (IV) Complex‐Based Delivery Systems to Improve Platinum (II) Anticancer Therapy

Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain

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