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:10.1186/1471-2407-13-495

Cited by 22 publications

(25 citation statements)

References 23 publications

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“…For instance, calcium and magnesium (Ca/Mg) infusions were recommended as an effective method to reduce oxaliplatin-induced neurotoxicity, 58 but recent phase I and II studies demonstrated that Ca/Mg infusions did not seem to prevent acute neurotoxicity of oxaliplatin. 57,58 In addition, the biotransformation in the bloodstream also contributes to the side effects of platinum (II) complex. 59 For example, Sooriyaarachchi et al focused on the mechanism of sodium thiosulfate (STS) modulated metabolism of cisplatin in human plasma in vitro.…”

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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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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“…Results of several recent randomized clinical trials testing the effectiveness of calcium/magnesium infusion to counteract acute OHP neurotoxicity are available [ 93 , 94 , 95 ].…”

Section: Main Mechanisms Of Platinum Drug Neurotoxicitymentioning

confidence: 99%

“…Despite a theoretical basis for the use of this kind of neuroprotection, the overall results and in particular the two most recent trials [ 94 , 95 ] failed to demonstrate a real protection of calcium/magnesium infusion in acute OHP neurotoxicity.…”

Section: Main Mechanisms Of Platinum Drug Neurotoxicitymentioning

confidence: 99%

Current View in Platinum Drug Mechanisms of Peripheral Neurotoxicity

Chiorazzi

Semperboni

Marmiroli

2015

Toxics

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Peripheral neurotoxicity is the dose-limiting factor for clinical use of platinum derivatives, a class of anticancer drugs which includes cisplatin, carboplatin, and oxaliplatin. In particular cisplatin and oxaliplatin induce a severe peripheral neurotoxicity while carboplatin is less neurotoxic. The mechanisms proposed to explain these drugs’ neurotoxicity are dorsal root ganglia alteration, oxidative stress involvement, and mitochondrial dysfunction. Oxaliplatin also causes an acute and reversible neuropathy, supposed to be due by transient dysfunction of the voltage-gated sodium channels of sensory neurons. Recent studies suggest that individual genetic variation may play a role in the pathogenesis of platinum drug neurotoxicity. Even though all these mechanisms have been investigated, the pathogenesis is far from clearly defined. In this review we will summarize the current knowledge and the most up-to-date hypotheses on the mechanisms of platinum drug-induced peripheral neurotoxicity.

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“…To mimic clinically achievable oxaliplatin exposures in vitro, cells were treated for 3 h with 10, 30 and 100 lM oxaliplatin. Considering the rate of oxaliplatin degradation in supplemented Neurobasal-A medium (t 1/2 % 3 h; Figure S1), determining by HPLC (Ip et al 2008), these in vitro treatments equated to AUCs for oxaliplatin exposure of 21.7, 65 and 217 lM.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 2013). Representative images suggested the presence of Fig.…”

Section: Effects Of Oxaliplatinmentioning

confidence: 99%

“…To investigate this hypothesis, we established a click chemistry 5-ethynyluridine (EU) RNA incorporation fluorescence labelling assay to visualize and measure global transcriptional activity (Jao and Salic 2008) in individual DRG neurons in vitro, and related these measurements to those of neuronal cell body size. 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 2013). 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 2008).…”

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confidence: 99%

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

Cited by 22 publications

References 23 publications

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

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

Current View in Platinum Drug Mechanisms of Peripheral Neurotoxicity

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

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