IADR Abstract Archives
DMPS and DMSA Prevent Cisplatin-induced Renal Dysfunction
Objectives: Sodium 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercapto- succinic acid (DMSA) are organosulfur compounds which form complexes with various heavy metals. Previously, we reported that despite acting as an antidote to heavy metal intoxication, lower doses of DMPS inversely enhanced cisplatin (CDDP)-induced antitumor activity in S-180 cell-bearing mouse model. This activity was only weak with DMSA, however (Sato T. et al., J Pharmacol Sci. 2010). The purpose of the present study was to investigate the effects of lower doses of DMPS or DMSA on the nephrotoxicity and kinetics of CDDP.
Methods: Female SPF ddy-mice weighing 25-30 g each were used. All experiments were performed in accordance with the Ethical Guidelines for Animal Experiments at Tokyo Dental College. CDDP with or without DMPS or DMSA was administered in each animal once daily for 4 days. On day 5, 7, or 9 after commencing administration, the kidneys and blood were isolated under deep anesthesia and blood urea nitrogen (BUN) and transporter protein OCT2 and MATE1 mRNA levels measured. TUNEL staining of renal tubule cells and CDDP-originated platinum levels in plasma and organ were also determined.
Results: The results revealed that DMPS or DMSA significantly reduced CDDP-induced increases in BUN. Moreover, DMPS or DMSA decreased platinum levels in renal tissues, but not in blood. The mRNA levels of OCT2 and MATE-1 were significantly decreased by CDDP in renal tissues. Administration of DMPS or DMSA ameliorated this reduction in these transporters. Cisplatin-induced apoptosis in renal tissue as determined by TUNEL staining was reduced by administration of DMPS or DMSA.
Conclusions: These results suggest that DMPS or DMSA has the potential to neutralize the nephrotoxicity of CDDP by enhancing transporter protein production and the formation of organic platinum complexes.
Methods: Female SPF ddy-mice weighing 25-30 g each were used. All experiments were performed in accordance with the Ethical Guidelines for Animal Experiments at Tokyo Dental College. CDDP with or without DMPS or DMSA was administered in each animal once daily for 4 days. On day 5, 7, or 9 after commencing administration, the kidneys and blood were isolated under deep anesthesia and blood urea nitrogen (BUN) and transporter protein OCT2 and MATE1 mRNA levels measured. TUNEL staining of renal tubule cells and CDDP-originated platinum levels in plasma and organ were also determined.
Results: The results revealed that DMPS or DMSA significantly reduced CDDP-induced increases in BUN. Moreover, DMPS or DMSA decreased platinum levels in renal tissues, but not in blood. The mRNA levels of OCT2 and MATE-1 were significantly decreased by CDDP in renal tissues. Administration of DMPS or DMSA ameliorated this reduction in these transporters. Cisplatin-induced apoptosis in renal tissue as determined by TUNEL staining was reduced by administration of DMPS or DMSA.
Conclusions: These results suggest that DMPS or DMSA has the potential to neutralize the nephrotoxicity of CDDP by enhancing transporter protein production and the formation of organic platinum complexes.