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Disodium 2,2′-dithio-bis-ethane sulfonate (BNP7787) is under investigation as a potential new chemoprotector against cisplatin-induced nephrotoxicity. The selective protection of BNP7787 appears to arise from the preferential uptake of the drug in the kidneys, where BNP7787 would undergo intracellular conversion into mesna (2-mercapto ethane sulfonate), which in turn can prevent cisplatin induced toxicities. In the present study, we have investigated whether the reduction of BNP7787 into the reactive compound mesna is restricted to the kidney or whether it can also occur in other organs, cells and physiological compartments, including the cytosolic fraction of the renal cortex, plasma, red blood cells (RBCs), liver and small intestine from rats and several tumors (OVCAR-3, MRI-H-207 and WARD). We also determined whether the endogenous thiols glutathione (GSH) and cysteine and the enzyme systems glutaredoxin and thioredoxin, which are all present in the kidney, can be involved in the BNP7787 reduction. UV detection and micro-HPLC with dual electrochemical detection were used to analyze the various incubation mixtures. Our observations are that, in contrast to plasma, a very large reductive conversion of BNP7787 to mesna was measured in RBC lysate. Intact RBCs, however, did not take up BNP7787. Although BNP7787 could be reduced in cytosol of liver and several tumors, this reduction will not be relevant in vivo, since these tissues do not take up large amounts of BNP7787. Kidney cortex cytosol was, similar to the small intestine cytosol, able to substantially reduce BNP7787 to mesna. The ability to reduce BNP7787 in the presence of the endogenous thiols GSH and cysteine, the glutaredoxin system as well as the thioredoxin system, could at least in part explain the high BNP7787 reductive activity of the kidney cortex cytosol. In conclusion, the high reduction of BNP7787 into mesna in the kidney as well as our earlier observation that the distribution of BNP7787 and mesna was mainly restricted to rat kidney are strong arguments in favor of selective protection of the kidney by BNP7787. [Copyright &y& Elsevier]

Purpose. BNP7787 is a new chemoprotective agent presently under clinical investigation to protect against cisplatin-induced toxicities, especially nephrotoxicity and neurotoxicity. In the kidneys BNP7787 is postulated to undergo selective conversion into mesna, which can locally detoxify cisplatin. The reactivity of cisplatin with this new chemoprotective agent and with its metabolite mesna was investigated at clinically observed plasma concentrations and compared with the nucleophiles thiosulfate (TS) and DDTC, and with the endogenous compounds glutathione (GSH) and oxidized glutathione (GSSG). Methods. Reaction kinetics experiments were performed at 37°C and pH 7.4 in the presence of a high chloride concentration (0.15 M). The degradation of cisplatin was measured over time using HPLC with off-line flameless atomic absorption spectrophotometry. Results. The degradation half-lives of cisplatin (13.5 μM) with 17.2 mM BNP7787, 340 μM mesna and 17.2 mM mesna were 124 min, about 790 min and 73 min, respectively. Cisplatin reacted at least 9.5 times more slowly with 17.2 mM BNP7787 and 5.5 times more slowly with 17.2 mM mesna than with 17.2 mM of the modulating agents DDTC or TS (i.e. half-lives 11 and 13 min, respectively). The half-lives of cisplatin with 17.2 mM GSH and GSSG (i.e. 122 and 115 min, respectively) were comparable with the half-life obtained with BNP7787. The thiol mesna was shown to be a stronger nucleophile than its corresponding disulfide BNP7787. Conclusions. The much slower relative reactivity of BNP7787, the short residence of BNP7787 (approximately 2 h) and the much lower concentration of mesna in the circulation following BNP7787 administration precludes chemical inactivation of cisplatin in the circulation, and thus the antitumor activity of cisplatin is maintained. [ABSTRACT FROM AUTHOR]