NDLI: The effect of sodium thiosulfate on the metabolism of cis-platin in human plasma in vitro

Content Provider	Royal Society of Chemistry (RSC)
Author	Sooriyaarachchi, Melani Narendran, Aru Gailer, Jürgen
Copyright Year	2012
Abstract	The anticancer drug cis-platin (CP) is widely used to treat patients, but it is also associated with significant side effects, including nephrotoxicity. Given that this metallodrug is intravenously (iv) administered, its biotransformations in the bloodstream are likely to be involved in mediating these side-effects. Previous studies have revealed that the iv administration of patients/mammalian model organisms with sodium thiosulfate (STS) can ameliorate the side effects of CP, but the underlying molecular basis remains elusive. We have studied the effect of STS on the metabolism of CP in human plasma in vitro by determining the platinum (Pt) distribution using size exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma atomic emission spectrometer (ICP-AES). The addition of STS to plasma 10 min before CP was added accelerated the hydrolysis of CP and resulted in the formation of a Pt–STS complex. Conversely, when plasma was incubated with CP for up to 3 h and STS was added thereafter the analysis of the obtained mixture revealed that the formation of the same Pt–STS complex which in turn greatly diminished the plasma protein binding of CP-derived hydrolysis products. Thus, the observed amelioration of the side effects of CP by STS can be rationalized in terms of the rapid formation of a biologically inactive Pt–STS complex in the bloodstream. This is the first mechanism that can explain the amelioration of the side effects of CP by STS. Based on the fact that cis-platin remained in plasma for a considerable amount of time, the optimization of the administration sequence, the molar ratio and the time delay between the administration of both drugs emerges as a viable strategy to achieve a careful balance between ameliorating the side effects while leaving the antitumour activity intact. Our results demonstrate that in vitro studies can be useful to develop feasible strategies to mitigate the side-effects of Pt-based anticancer drugs in patients.
Starting Page	960
Ending Page	967
Page Count	8
File Format	HTM / HTML PDF
ISSN	17565901
Volume Number	4
Issue Number	9
Journal	Metallomics
DOI	10.1039/c2mt20076g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Plasma protein binding Inductively coupled plasma atomic emission spectroscopy Concentration Metabolism Spectrometer Cisplatin Blood plasma SEC Hydrolysis Inductively coupled plasma Size-exclusion chromatography U.S. Securities and Exchange Commission Nephrotoxicity Sodium thiosulfate Mathematical optimization
Content Type	Text
Resource Type	Article
Subject	Chemistry Medicine Metals and Alloys Biochemistry Biomaterials Biophysics

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