Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin

Screnci, D.; Er, Hui Meng; Hambley, Trevor W.; Galettis, Peter; Brouwer, W.; McKeage, Mark J.

doi:10.1038/bjc.1997.416

Cited by 32 publications

(33 citation statements)

References 21 publications

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“…Neurotoxicity is the dose-limiting clinical side effect of oxaliplatin (Grothey, 2003). In previous studies, oxaliplatin neurotoxicity was associated with accumulation of platinum by DRG tissue and its sensory neurons in female Wistar rats or related animal models (Screnci et al, 1997(Screnci et al, , 2000Holmes et al, 1998;Luo et al, 1999;Ta et al, 2006). In the current study, DRG tissue and primary cultures from female Wistar rats were first shown to have significant mRNA expression and functional activity of rOctn1 and rOctn2.…”

Section: Discussionmentioning

confidence: 99%

“…Platinum accumulation within the dorsal root ganglion (DRG) and its sensory neurons is a major determinant of the neurotoxicity of oxaliplatin (Screnci et al, 1997(Screnci et al, , 2000Holmes et al, 1998;Luo et al, 1999;Ta et al, 2006). The biological processes responsible for platinum accumulation in DRG tissue and neurons are poorly understood, although candidate membrane transporters have been identified on the basis of their ability to transport platinum complexes in other cell types (Hall et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Then we studied the mRNA expression of rOctn1 and rOctn2 in DRG tissues from adult female Wistar rats compared with that in other normal tissues and that of rOcts. Adult female Wistar rats were used as a source of tissues because of the existence of a large body of published work on the neurotoxicity of oxaliplatin and other platinum drugs in this specific animal model to which transporter expression profiles to be generated could subsequently be related (Screnci et al, 1997(Screnci et al, , 2000Cavaletti et al, 2001;Pisano et al, 2003;Ghirardi et al, 2005;Liu et al, 2009). Then, we studied the functional activity of rOctns and rOcts in primary cultures of rat DRG neurons from postnatal female Wistar rats, by measuring uptake of radiolabeled model OCTN and OCT substrates including TEA ϩ , MPP ϩ , L-carnitine, and ergothioneine.…”

Section: Introductionmentioning

confidence: 99%

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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

114

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

114

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“…The R,R-and S,S-enantiomers of ormaplatin ((DACH)PtCl 4 ) and oxaliplatin ((DACH)Pt(oxalato)) were synthesized as outlined previously (Screnci et al, 1997). JM216 was kindly provided by the Johnson Matthey Technology Centre (Reading, UK).…”

Section: Drugs (Table 1 Figure 1)mentioning

confidence: 99%

“…To test this hypothesis, we measured the hydrophobicity of a series of eight platinum drugs, and in an extension to our previous studies (McKeage et al, 1994;Screnci et al, 1997), we measured the potency of a series of compounds for altering sensory nerve conduction velocity (SNCV) in Wistar rats treated on a twice per week dosing schedule at the maximum tolerated dose (MTD). We measured the concentrations of platinum in various tissues from the nervous system of rats treated with different platinum derivatives using an inductively coupled plasma mass spectrometry (ICP-MS) technique developed in our laboratory (Screnci et al, 1998) and the reactivity of the compounds to plasma proteins.…”

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confidence: 99%

Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs

et al. 2000

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Previous work has shown platinum drugs to differ in their effects on the peripheral nervous system. To test whether their differential toxicity was due to differences in their partitioning into the peripheral nervous system, we correlated the hydrophobicity, reactivity, tissue accumulation and neurotoxicity of a series of eight platinum analogues. Neurotoxicity was detected by measuring sensory nerve conduction velocity (SNCV) in Wistar rats treated twice per week at the maximum tolerated dose. Tissue platinum concentrations were measured by inductively coupled plasma mass spectrometry. Hydrophobicity (log P) was measured using an octanol-aqueous shake-flask method. The half-life of platinum drug binding to plasma proteins in vitro was determined. The cumulative dose causing altered SNCV ranged from 15 to > 2050 μmol kg −1 . Ranking of the compounds by their neurotoxic potency in rats (oxaliplatin > R,R -(DACH)PtC 4 > ormaplatin > S,S -(DACH)PtCl 4 > S,S -(DACH)Pt oxalato > cisplatin > carboplatin > JM216) correlated with the frequency of neurotoxicity in patients ( r > 0.99; P < 0.05). Ranking the compounds by their peripheral nerve accumulation was cisplatin > carboplatin > oxaliplatin > R,R -(DACH)PtCl 4 ≈ S,S -(DACH)PtCl 4 and did not correlate with neurotoxicity. Log P ranged from – 2.53 to –0.16 but did not correlate with neurotoxicity. Log P correlated inversely with platinum accumulation in dorsal root ganglia (r 2 = 0.99; P = 0.04), sural nerve (r 2 = 0.85; P = 0.025), sciatic nerve (r 2 = 0.98; P = 0.0012), spinal cord (r 2 = 0.97, P = 0.018) and brain (r 2 = 0.98, P = 0.001). Reactivity correlated with neurotoxicity potency in rats (r 2 = 0.89, P = 0.0005) and with the frequency of neurotoxicity in patients (r 2 = 0.99, P = 0.0002). The hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system but not with neurotoxicity. Differences in the reactivity of platinum complexes accounts for some of the variation in their neurotoxicity. © 2000 Cancer Research Campaign

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Mechanisms of reaction ofL-methionine with carboplatin and oxaliplatin in different media: a comparison with cisplatin

Heudi

Mercier-Jobard

Cailleux

et al. 1999

Biopharm. Drug Dispos.

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The activity of platinum compounds is dependent on nucleophile substitution reactions. In this paper, we study the reactivity of L‐met with carboplatin, oxaliplatin and cisplatin by following with HPLC‐UV the concentration of L‐met and by characterizing the resulting adducts with LC‐MS. In the absence of NaCl, in water, the initial rate at which L‐met concentration decreases with cisplatin, oxaliplatin and carboplatin is 0.25±0.007, 0.057±0.01 and 0.17±0.02 mM h−1, respectively. In phosphate buffer this rate is 0.056±0.009 for cisplatin, 0.019±0.001 and 0.13±0.02 for carboplatin and oxaliplatin, respectively. Reactions of L‐met with cisplatin occurred via its conversion into monoaqua species in water and into phosphato‐derivatives (AP) in phosphate buffer but finally the same methionine–platinum adducts M2 [(NH3)2(met)]Pt, M4 and M5 [(met)2]Pt were characterized. Reaction of carboplatin with l‐met occurred via the formation of M0 [(NH3)2(met)(CBDCA)]Pt whose structure is consistent with the direct interaction of L‐met with carboplatin. However, the same final products as those found with cisplatin were characterized. The reaction of oxaliplatin with L‐met proceeded through a mechanism similar to that of carboplatin to give M7 [(met)(DACH)]Pt. In the presence of NaCl, cisplatin directly reacted with L‐met to yield at least five methionine–platinum adducts. The reaction of carboplatin gave the same adducts suggesting its transformation into cisplatin. The reaction of oxaliplatin with L‐met occurred via the formation of aquated species A [(OH)(Cl)(DACH)]Pt which readily underwent reaction with L‐met to form M6 [(met)(Cl)(DACH)]Pt and M7. This study shows that the reactivity of cisplatin, carboplatin and oxaliplatin is dependent on the media in which they occur. The discrepancy between their reactions with L‐met could partly explain their therapeutic differences. Copyright © 1999 John Wiley & Sons, Ltd.

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Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin

Cited by 32 publications

References 21 publications

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

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

Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs

Mechanisms of reaction ofL-methionine with carboplatin and oxaliplatin in different media: a comparison with cisplatin

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