Platinum-specific detection and quantification of oxaliplatin and Pt(R,R-diaminocyclohexane)Cl2 in the blood plasma of colorectal cancer patients

Ip, Virginia; McKeage, Mark J.; Thompson, Paul; Damianovich, Dragan; Findlay, Michael; Liu, JJ

doi:10.1039/b716925f

Cited by 25 publications

(27 citation statements)

References 17 publications

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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%

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: Effects Of Oxaliplatinmentioning

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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“…Second, tissue-selective expression profiles of oxaliplatin transporters such as that described in this article could be exploited to selectively reduce oxaliplatin-induced neurotoxicity because OCTs rather than OCTNs appear to contribute to oxaliplatin uptake and antitumor activity in colorectal carcinoma (Zhang et al, 2006;Yokoo et al, 2008), the major current clinical indication for oxaliplatin. Last, only transient and intermittent OCTN1 inhibition may be required to protect against oxaliplatin-induced neuropathy because oxaliplatin has a very short plasma half-life (Ip et al, 2008) and is given only once every 2 to 3 weeks. However, if OCTN1 is involved in the excretion of oxaliplatin, its inhibition might result in a pharmacokinetic drug-drug interaction leading to increased toxicity.…”

Section: Octns Mediate Oxaliplatin Uptake 545mentioning

confidence: 99%

Oxaliplatin Transport Mediated by Organic Cation/Carnitine Transporters OCTN1 and OCTN2 in Overexpressing Human Embryonic Kidney 293 Cells and Rat Dorsal Root Ganglion Neurons

Jong¹,

Nakanishi²,

Liu³

et al. 2011

J Pharmacol Exp Ther

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115

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The organic cation/carnitine transporters OCTN1 and OCTN2 are related to other organic cation transporters (OCT1, OCT2, and OCT3) known for transporting oxaliplatin, an anticancer drug with dose-limiting neurotoxicity. In this study, we sought to determine whether OCTN1 and OCTN2 also transported oxaliplatin and to characterize their functional expression and contributions to its neuronal accumulation and neurotoxicity in dorsal root ganglion (DRG) neurons relative to those of OCTs. [ 14 C]Oxaliplatin uptake, platinum accumulation, and cytotoxicity were determined in OCTN-overexpressing human embryonic kidney (HEK) 293 cells and primary cultures of rat DRG neurons. Levels of mRNA and functional activities of rat (r)Octns and rOcts in rat DRG tissue and primary cultures were characterized using reverse transcription-polymerase chain reaction and uptake of model OCT/OCTN substrates, including [ showed increased uptake and cytotoxicity of oxaliplatin compared with mock-transfected HEK293 controls; in addition, both uptake and cytotoxicity were inhibited by ergothioneine and L-carnitine. The uptake of ergothioneine mediated by OCTN1 and of L-carnitine mediated by OCTN2 was decreased during oxaliplatin exposure. rOctn1 and rOctn2 mRNA was readily detected in rat DRG tissue, and they were functionally active in cultured rat DRG neurons, more so than rOct1, rOct2, or rOct3. DRG neuronal accumulation of [ 14 C]oxaliplatin and platinum during oxaliplatin exposure depended on time, concentration, temperature, and sodium and was inhibited by ergothioneine and to a lesser extent by L-carnitine but not by MPP ϩ . Loss of DRG neuronal viability during oxaliplatin exposure was inhibited by ergothioneine but not by L-carnitine or MPP ϩ . OCTN1 and OCTN2 both transport oxaliplatin and are functionally expressed by DRG neurons. OCTN1-mediated transport of oxaliplatin appears to contribute to its neuronal accumulation and treatmentlimiting neurotoxicity more so than OCTN2 or OCTs.

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“…Ratios of their pharmacokinetic parameters were close to unity and their respective 90% CIs fell within predefined no-effect boundaries of 0.8 and 1.25. We found intact oxaliplatin to be the major platinum species freely circulating in the plasma after oxaliplatin treatment, accounting for approximately 75% and 80% of the free platinum AUC 0-t and C max , respectively, as previously reported [17,21]. The only other study that we are aware of that attempted to compare the plasma pharmacokinetics of platinum in patients given oxaliplatin with or without Ca/Mg infusions was reported by Ishibashi et al [22].…”

Section: Discussionmentioning

confidence: 57%

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

Han

Khwaounjoo

Kilfoyle

et al. 2014

JCO

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Platinum-specific detection and quantification of oxaliplatin and Pt(R,R-diaminocyclohexane)Cl2 in the blood plasma of colorectal cancer patients

Cited by 25 publications

References 17 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

Oxaliplatin Transport Mediated by Organic Cation/Carnitine Transporters OCTN1 and OCTN2 in Overexpressing Human Embryonic Kidney 293 Cells and Rat Dorsal Root Ganglion Neurons

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

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