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Peripheral neuropathy and cognitive impairments following cisplatin administration may interfere with the clinical usage of the drug. Mesna is a chemoprotective agent with anti-inflammatory and anti-oxidant effects. Our study aimed to investigate the protective effects of mesna against cisplatin-induced neurotoxicity. Neurotoxicity was induced by the administration of 2.5 mg/kg cisplatin twice a week for four consecutive weeks in male Wistar rats. The neuroprotective effect of mesna (150 mg/kg/day) was evaluated through behavioral, electrophysiological, and molecular studies. Cisplatin treatment caused passive avoidance memory impairment, increased anxiety-like behaviors, altered thermal sensitivity, and decreased muscle strength in a grip strength test. Our electrophysiological studies indicated that administration of cisplatin induced peripheral sensory neuropathy and decreased the amplitudes of the compound action potential of sensory nerves. Cisplatin administration increased MDA and 4-HNE levels and decreased anti-oxidant (SOD and GPx) enzymes. Proinflammatory cytokines (IL-1β and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were increased by cisplatin treatment. Morphological alterations were observed in the dorsal root ganglion (DRG) of cisplatin-treated rats. Cognitive impairments, anxiety, muscle strength, and thermal sensitivity changes induced by cisplatin were improved with mesna treatment. The reduced conduction velocity in sensory nerves was recovered in the cisplatin + mesna group. Mesna partially alleviated redox imbalance, reduced the proinflammatory cytokines, and MMP-2/9 levels. Mesna administration also relieved the morphological changes in DRG of cisplatin-treated rats. In conclusion, our results revealed that mesna can alleviate cisplatin-induced central and peripheral nervous system toxicity. These results support the concept that chemotherapy-induced neuropathy can be partially inhibited via mesna.

Purpose: Previous studies from our laboratory have identified a role for gamma-glutamyl transpeptidase (GGT) in BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate, dimesna, Tavocept™)-mediated cisplatin nephroprotection. Dekant has proposed that gamma-glutamyl transpeptidase (GGT), aminopeptidase N (APN) and cysteine-conjugate-β-lyase (CCBL) comprise a multi-enzyme pathway that acts on xenobiotic-glutathione conjugates converting them to nephrotoxic metabolites. We report modulation of APN activity within this pathway by BNP7787-derived mesna-disulfide heteroconjugates., Methods: A fluorimetric assay was used to determine the effect of BNP7787, BNP7787-derived mesna-disulfide heteroconjugates, and the BNP7787 metabolite, mesna (sodium 2-mercaptoethane sulfonate), on the initial velocity and overall progress curve of the human APN reaction in vitro., Results: Neither BNP7787 nor mesna-cysteinyl-glutamate inhibited human APN. Select BNP7787-derived mesna-disulfide heteroconjugates (mesna-cysteine, mesna-glutathione, mesna-cysteinyl-glycine) and high concentrations of mesna inhibited APN activity. Allosteric effects on the enzyme progress curve outside of the linear initial velocity region were observed for mesna-cysteinyl-glycine, mesna-glutathione and mesna-cysteinyl-glutamate and appeared to be a function of having both mesna and di- or tri-peptide functionalities in one molecule. In situ-generated mesna-cisplatin conjugates were not a substrate for human APN., Conclusions: BNP7787-mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve APN inhibition by certain BNP7787-derived mesna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for BNP7787-mediated nephroprotection of cisplatin-induced nephrotoxicity involving the GGT, APN and CCBL nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity.

Taxane and platinum drugs are important agents in the treatment of cancer and have shown activity against a variety of tumors, including ovarian, breast, and lung cancer, either as single agents or in combination with other chemotherapy drugs. However, a serious and prevalent side effect of taxane (docetaxel and all formulations/derivatives of paclitaxel) and platinum (cisplatin, carboplatin, and oxaliplatin) agents is dose-limiting chemotherapy-induced peripheral neuropathy (CIPN). CIPN can result in treatment delays, dose modifications, and, in severe cases, discontinuation of chemotherapy. Consequently, effective treatments for CIPN are needed. Dimesna (BNP7787; Tavocept; disodium 2,2'-dithio-bis-ethanesulfonate) is an investigational drug that is undergoing international clinical development as a treatment that is coadministered with first-line taxane and platinum combination chemotherapy in patients with inoperable advanced primary adenocarcinoma of the lung. BNP7787 is currently being developed with the objective of increasing the survival of cancer patients receiving taxane- and/or cisplatin-based chemotherapy. Additional data indicate that BNP7787 may also protect against common and serious chemotherapy-induced toxicities, including chemotherapy-induced anemia, nausea, emesis, nephrotoxicity, and neuropathy, without interfering with antitumor activity of the chemotherapeutic agent(s). Studies herein show that BNP7787 prevents aberrant microtubule protein (MTP) polymerization that is caused by exposure of MTP to paclitaxel or cisplatin. BNP7787 modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of BNP7787, protects against time-dependent cisplatin-induced inactivation of MTP. We propose that interactions between BNP7787 and MTP may play a role in BNP7787-mediated protection against CIPN.

Purpose: The mechanisms for cisplatin-induced renal cell injury have been the focus of intense investigation for many years with a view to provide a more effective and convenient form of nephroprotection. BNP7787 (disodium 2,2'-dithio-bis ethane sulfonate; dimesna, Tavocept), is a water-soluble disulfide investigational new drug that is undergoing clinical development for the prevention and mitigation of clinically important chemotherapy-induced toxicities associated with platinum-type chemotherapeutic agents. We hypothesized that part of BNP7787's mechanism of action (MOA) pertaining to the potential prevention of cisplatin-induced nephrotoxicity involves the inhibition of gamma-glutamyl transpeptidase (GGT) activity, mediated by BNP7787-derived mesna-disulfide heteroconjugates that contain a terminal gamma-glutamate moiety [e.g., mesna-glutathione (MSSGlutathione) and mesna-cysteinyl-glutamate (MSSCE)]., Methods: Inhibition studies were conducted on human and porcine GGT to determine the effect of mesna-disulfide heteroconjugates on the enzyme's activity in vitro. These studies utilized a fluorimetric assay that monitored the hydrolysis of L-gamma-glutamyl-7-amino-4-trifluoromethylcoumarin (GG-AFC) to AFC., Results: Mesna-disulfide heteroconjugates that contained gamma-glutamyl moieties were potent inhibitors of human and porcine GGT. An in situ-generated mesna-cisplatin conjugate was not a substrate for GGT., Conclusions: The GGT xenobiotic metabolism pathway is postulated to be a major toxification pathway for cisplatin nephrotoxicity, and BNP7787 may play a novel and critical therapeutic role in the modulation of GGT activity. We further postulate that there are two general mechanisms for BNP7787-mediated nephroprotection against cisplatin-induced nephrotoxicity involving this pathway. First, the active BNP7787 pharmacophore, mesna, produces an inactive mesna-cisplatin conjugate that is not a substrate for the GGT toxification pathway (GGT xenobiotic metabolism pathway) and, second, BNP7787-derived mesna-disulfide heteroconjugates may serve as selective, potent inhibitors of GGT, possibly resulting in nephroprotection by a novel means.

Objective: The hypothesis was that the administration of the antioxidant mesna (sodium 2-mercaptoethanesulfonate) during chemotherapy would protect ovaries against follicular damage., Study Design: Sprague-Dawley rats were treated with saline solution, mesna-plus-cisplatin, or cisplatin. Immunohistochemistry was used to evaluate the Müllerian inhibiting substance (MIS) positive follicles. Serum and ovarian MIS were measured with enzyme-linked immunosorbent assay and Western blot analysis, respectively. Apoptosis in ovaries was studied by terminal deoxynucleotidyl transfer biotin-d UTP nick end labeling (TUNEL) assay., Result: Immunofluorescence staining for MIS was higher in preantral follicles in the mesna-plus-cisplatin group. The ovarian and serum MIS levels were higher in the mesna-plus-cisplatin than in the cisplatin alone group. There were no differences statistically in the TUNEL and the ovarian cyst analyses., Conclusion: Mesna, which was used at the time of cisplatin administration, protected ovaries against damage. The data that are presented challenge the existing clinical paradigm that gonadotropin-releasing hormone agonists represent the only medical method for the protection of ovaries during chemotherapy. Alternative medical means to protect ovaries during chemotherapy may be achievable.

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.

In preclinical studies, BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate), the disulphide form of mesna, has demonstrated selective protection against cisplatin-induced nephrotoxicity due to conversion into mesna inactivating toxic platinum species. Mesna (sodium 2-mercapto ethane sulphonate), however, can affect the antitumour activity of cisplatin, while BNP7787 does not interfere with the antitumour activity. To understand the difference in interference with cisplatin-induced antitumour activity between BNP7787 and mesna as well to characterise the selective nephroprotection by BNP7787, the pharmacokinetics of BNP7787 and mesna, each given i.v. 1000 mg x kg(-1), were determined in plasma, kidney, liver, red blood cells (RBC), skeletal muscle and tumour of Fischer rats bearing subcutaneously implanted WARD colon tumours. The following results were obtained: (1). high concentrations of BNP7787 and mesna were observed in the plasma and kidney after administration of BNP7787 or mesna, except for mesna in plasma after BNP7787 administration; (2). in all other sampled compartments, the AUC values of both compounds were at least 5.5-fold lower than the corresponding values in kidney; (3). the AUC of mesna in plasma after mesna administration was comparable to the AUC of mesna in kidney after a dose of BNP7787 that can completely prevent cisplatin-induced nephrotoxicity in rats; (4). the AUC of mesna in plasma was five-fold higher relative to the AUC of mesna following BNP7787 administration (P<0.01). In conclusion, the five-fold higher AUC of mesna in plasma after mesna administration and the fact that mesna is more reactive with (hydrated) cisplatin than its disulphide form BNP7787 represent a plausible explanation as to why mesna administration can reduce the antitumour activity of cisplatin. After BNP7787 administration, the distribution of BNP7787 and mesna was restricted to the kidney, which confirmed the selective protection of the kidney by BNP7787.

BNP7787 (2',2'-dithio-bis-ethane sulphonate sodium), a water-soluble disulphide, is chemically and mechanistically different from other sulphur-containing chemoprotective agents. Presently, BNP7787 is under investigation for its protective properties with regard to the side-effects of platinum compounds. In this study, we evaluated BNP7787, mesna and amifostine for their effects on the antitumour activity of platinum compounds. Continuous exposure to BNP7787 did not affect the antiproliferative effects of cisplatin or carboplatin, but the efficacy of both compounds was reduced in the presence of mesna in vitro in two human ovarian cancer cell lines. BNP7787 or amifostine combined with cisplatin or carboplatin given in standard schedules for the treatment of nude mice bearing well-established OVCAR-3 xenografts did not interfere with platinum-induced inhibition of tumour growth. Of interest, BNP7787 or amifostine co-administered with carboplatin was significantly more effective than carboplatin alone (P<0.01). In the presence of amifostine, doses of cisplatin and carboplatin could be safely increased by factors of 1.6 and 1.5, respectively. Unlike in a previous study of BNP7787 in tumour-bearing rats, BNP7787 did not protect against additional weight loss following treatment with higher doses of cisplatin in OVCAR-3-bearing mice. Pharmacokinetics of (mixed) disulphides including BNP7787 and extractable mesna in deproteinised plasma revealed a rapid disappearance of BNP7787 and an AUC(5-60) value of mesna 9-fold lower than that calculated after an equivalent dose of mesna by weight. We can conclude that BNP7787 does not interfere with the antitumour activity of platinum compounds in vitro and in vivo. Clinical trials are underway to evaluate the protection of normal tissues by BNP7787 when combined with cisplatin.

Background: Platinum agents are frequently combined with ifosfamide. Mesna, originally coadministered to protect from ifosfamide side effects, might also react with the platinum agents in these combinations., Methods: Malignant glioma cells were incubated with cisplatin, carboplatin and mesna. Cell numbers were measured by counting and by MTT-tests., Results: In cell free solution mesna turned MTT to its blue farmazan product. Mesna's effect on cells were cell-line specific: It penetrated U87 cells without effect on growth, reduced cell numbers in C6 and T98G cells and did not alter U251 cells. The concentration of cisplatin killing 50% of the cells were 7 x 10(-7) in C6, 9.7 x 10(-6) in T98G, 1.2 x 10(-5) in U251 and 2.4 x 10(-4) in U87 cells. For the same effect, carboplatin required 3-10 times higher concentrations. Mesna protected all cell lines from the cytotoxicity of the platinum agents., Conclusion: Clinical studies should specify in detail, infusion schedules of mesna and platinum agents.

Nephrotoxicity is a relatively common and potentially serious adverse effect of treatment with certain cytotoxic drugs (especially ifosfamide). The patient may develop severe chronic proximal tubular toxicity. It is therefore very important to attempt to reduce the frequency and severity of acute and chronic nephrotoxicity resulting from chemotherapy. A logical approach is described, with particular reference to ifosfamide and cisplatin, involving improved evaluation of the important clinical features of nephrotoxicity and a greater understanding of its pathogenesis. This approach will facilitate the development of logical preventive strategies, or less toxic analogues, or both. The methods used may also enable prediction of the potential nephrotoxicity of newly developed cytotoxic agents.

The reactive and rapidly excreted thiol mesna (2-mercaptoethane-sulphonate sodium) has the potential to reduce the dose-limiting nephrotoxicity of cisplatin by chemical neutralisation of the latter in the kidney. The reaction kinetics of cisplatin with mesna and its disulphide, dimesna, was studied at 37 degrees C in unbuffered 0.15 mol/l NaCl (pH 5.3) and in 0.15 mol/l NaCl buffered with 0.02 mol/l Hepes (pH 7.4). The reaction mixtures were analysed for intact cisplatin. In the presence of mesna or dimesna 0.5 mol/l as anticipated in urine for conditions of renal protection, the half-life (t1/2) of 0.2 mmol/l cisplatin was less than 6 min. t1/2 of 151 and 629 min were found in the presence of mesna and dimesna concentrations of 5 mmol/l and 3 mmol/l, respectively, anticipated in plasma under conditions of renal protection. Cis-diamminemonoaquamonochloroplatinum(II) 0.2 mmol/l reacted rapidly with 50 mmol thiosulphate and 0.5 mol/l (di)mesna (t1/2 less than or equal to 1 min). This platinum species also reacted rapidly with 2.6 mmol/l thiosulphate (t1/2 less than 1 min), a concentration reached in plasma for conditions under renal protection. Reaction of the monoaquated form of cisplatin proceeded slowly in the presence of dimesna or mesna concentrations (less than 5 mmol/l), as anticipated in plasma under renal protecting conditions. It is hypothesised that renal protection by the strong nucleophiles, thiosulphate, mesna and dimesna occurs rather by neutralisation of the aquated species in the lumen of the renal tubulus than by neutralisation of intact cisplatin, and that neutralisation of these species in plasma contributes significantly to the protecting effect.

Using simple kinetic modelling, we estimated the effect of nucleophilic (renal) protecting agents (thiosulfate, mesna, diethyldithiocarbamate) on the half-life and the area under the concentration-time curve (AUC) of cis-diamminedichloroplatinum(II) (CDDP) in plasma and peritoneum. Our basic assumptions were that (a) under non-protecting conditions, the elimination of intact CDDP from plasma and peritoneum is a first-order process determined by the elimination-rate constant (k), and (b) under conditions of renal protection the elimination of CDDP is a first-order process determined by kCDDP,P = kCDDP+kN.[N], with kCDDP,P representing kCDDP under conditions of protection; kN, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration of N. Half-lives under conditions of protection were 0.693/kCDDP,P. AUCs were obtained by integration of the first-order equations. The inactivation-indicating parameter was defined as being the ratio of the AUC under protecting conditions to the AUC under non-protecting conditions (Rinact). Rinact is approximately given by kCDDP/kCDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m-2h), the estimates of Rinact were 0.61 in plasma and 0.7 in the peritoneal cavity for i.p. injected CDDP and 0.87 in plasma for i.v. CDDP, indicating inactivation of CDDP under such conditions. Estimates of Rinact were 0.84 or 0.96 in plasma and 0.87 in the peritoneal cavity for supposed conditions of renal protection by systemic mesna (4.4 g m-2 h), suggesting only minor inactivation of i.p. or i.v. injected CDDP under such conditions. Under reported conditions of protection achieved with 4.4 g m-2 h systemic diethyldithiocarbamate (DDTC). Rinact was greater than 0.65 or 0.87 in plasma and greater than 0.75 in the peritoneal cavity for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.

Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.

The possible protective action of sodium-2-mercaptoethanesulfonate (mesna) on hemotoxicity induced by anticancer drugs was tested in normal mice. Mesna (100 mg/kg b.w.) was injected i.v. 1 h before the i.v. administration of cyclophosphamide (10, 120, and 200 mg/kg b.w.), doxorubicin (4.32, 7.2, and 12 mg/kg b.w.) and cis-diamminedichloroplatinum (5.4, 9, and 15 mg/kg b.w.). Results show that in this experimental model mesna does not seem to protect against toxicity of the tested anticancer drug on hemopoietic progenitor cells.

Although mesna afforded protection against the cytotoxicity of cisplatin in Chinese hamster cells, line V-79-753B, in vitro, there was no evidence for protection against nephrotoxicity when this drug combination was examined in the rat. It seems likely that cisplatin-induced nephrotoxicity is mediated by intracellular events in kidney cells which cannot be inhibited by mesna possibly due to its presence within cells in vivo as the stable and unreactive disulphide. On the basis of these data it is unlikely that combinations of mesna and cisplatin will be of therapeutic benefit in man.

cis-Diamminedichloroplatinum (cis-platinum) is an effective and widely used antitumor drug. Patients receiving cis-platinum, however, experience very profound and long lasting gastrointestinal symptoms. The role of intestinal mucosal toxicity in the pathogenesis of these symptoms is unclear. In this study we have investigated the thiol-containing compound mesna (sodium-2-mercaptoethanesulfonate) as a potential antidote to cis-platinum-induced gastrointestinal tract damage. In mice, mesna caused a significant reduction in the gastrointestinal toxicity of cis-platinum assessed by electron microscopy, villus recovery rate, and by disaccharidase estimations. Mesna also significantly reduced serum creatinine levels following cis-platinum. Administration of mesna prior (or immediately following) a 67% lethal dose of cis-platinum protected 87-100% of the animals from the lethal effects. The antitumor efficacy of cis-platinum in L1210 leukemia bearing mice was not affected by coadministration of mesna indicating that the protective effect may be tissue specific. In addition this finding indicates that mesna has potential as an agent which may improve the therapeutic index of cis-platinum in clinical practice.