Ameliorating the toxic side-effects of cisplatin by systematically modulating its metabolism in human plasma with chemoprotective agents
Date
2015-04-20
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Abstract
Using size-exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma atomic emission spectrometer (ICP-AES), the effect of three chemoprotective agents − sodium thiosulfate (STS), N-acetyl-L-cysteine (NAC) and D-methionine − were investigated on the metabolism of the Pt-based anti-cancer drug cis-platin (CP) in human blood plasma in vitro. All three sulfur compounds resulted in the formation of Pt-S complexes independent of their order of addition to plasma while concomitantly reducing the plasma protein binding of CP-derived Pt species. Analogous experiments that were carried out with PBS-buffer instead of plasma allowed to gain more insight into the bioinorganic chemistry that unfolds in the absence of plasma proteins under physiologically similar conditions. Analysis of a PBS-buffer sample that was spiked with CP and STS by X-ray absorption spectroscopy revealed the presence of [Pt(S2O3)4]6- while the analysis of those corresponding to D-methionine and NAC by liquid chromatography coupled to electrospray ionization mass spectrometry revealed the presence of [Pt(NH3)Cl(D-methionine)]+, [Pt(D-methionine)2]+ and [(NAC)2Pt(NH3)2]-, respectively. Unlike CP, STS or D-methionine, NAC adversely effected the plasma protein distribution of Fe and Zn in a dose and a time dependent manner. Combined, the results present - for the first time - a feasible biomolecular mechanism by which these chemoprotective agents may reduce the CP-induced toxic side-effects in vivo. The unique capability of SEC-ICP-AES to simultaneously detect all Pt species in human plasma (CP, CP hydrolysis products and Pt-S complexes) suggests that the metabolism of CP can be deliberately modulated to develop strategies to reduce the severe toxic side-effects of this otherwise very effective anti-cancer drug in patients. Since combination therapy is a
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promising strategy to overcome drug resistance during chemotherapy and since SEC-ICP-AES allows to visualize the simultaneous metabolism of two metal-based anti-cancer drugs in human blood plasma, the latter was spiked with CP (Pt) and NAMI-A (Ru) and analysed over time. The results revealed that both drugs bind to the same apparent plasma proteins, but importantly, did not adversely affect each other’s metabolism in plasma which is promising with regard to investigating this particular drug combination in clinical studies with patients in the near future.
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Keywords
Chemistry--Analytical, Chemistry--Inorganic
Citation
Sooriyaarachchi, M. D. (2015). Ameliorating the toxic side-effects of cisplatin by systematically modulating its metabolism in human plasma with chemoprotective agents (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24783