γ-Glutamyl transpeptidase (γ-GT) [2]
- Renal drug transporters (OAT1, OAT3, OCT2, MATE1) [3]
- Microtubule proteins (tubulin) [1]

In vitro activity: Dimesna modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of Dimesna, protects against time-dependent cisplatin-induced inactivation of MTP. Dimesna -mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve aminopeptidase N (APN) inhibition by certain Dimesna -derived esna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for Dimesna -mediated nephroprotection of cisplatin-induced nephrotoxicity involving the gamma-glutamyl transpeptidase (GGT), APN and cysteine-conjugated-β-lyase (CCBL) nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity. Mesna and its dimer, Dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters reveal renal organic anion transporters OAT1, OAT3, and OAT4 are responsible for kidney-specific uptake of Dimesna. Uptake of Dimesna by OAT1, OAT3, and OAT4 is determined to be saturable with KM of 636 μM, 390 μM and 590 μM, respectively.

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Dimesna (BNP-7787) modulated paclitaxel- and cisplatin-induced aberrant microtubule polymerization in vitro. It reversed paclitaxel-induced excessive microtubule stabilization and cisplatin-induced microtubule depolymerization, restoring normal microtubule dynamics without directly altering tubulin polymerization in the absence of chemotherapeutic agents [1]
- Dimesna (BNP-7787) exhibited nephroprotective effects by inhibiting γ-GT activity in renal proximal tubular cells. It reduced cisplatin-induced reactive oxygen species (ROS) production and cell apoptosis, which was associated with decreased γ-GT-mediated activation of cisplatin toxicity [2]
- Dimesna (BNP-7787) was a substrate for renal organic anion transporters (OAT1, OAT3) and organic cation transporters (OCT2, MATE1). It showed concentration-dependent uptake in OAT1/OAT3-overexpressing cells, and its transport was inhibited by specific OAT/OCT/MATE inhibitors. No significant binding to plasma proteins was observed (protein binding < 10%) [3]

Tumors of urinary bladder induced by cyclophosphamide (CP) in rats can be significantly reduced by Dimesna administration in a dose-related manner.

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In cisplatin-induced nephrotoxicity rat models, intravenous administration of Dimesna (BNP-7787) (150 mg/kg, 30 minutes before cisplatin) reduced serum creatinine and blood urea nitrogen (BUN) levels, alleviated renal tubular necrosis, and decreased renal tissue ROS and apoptotic cell counts. It downregulated γ-GT expression in renal tissues and inhibited cisplatin-induced γ-GT activation [2]
- In cyclophosphamide-treated rats, Dimesna (BNP-7787) (100 mg/kg, intraperitoneal injection, 30 minutes before and 4 hours after cyclophosphamide) significantly reduced the incidence of urinary bladder tumors. It prevented cyclophosphamide-induced bladder mucosal damage and oxidative stress, without affecting the antitumor efficacy of cyclophosphamide [4]
- In rats, Dimesna (BNP-7787) was rapidly distributed to the kidneys and bladder after intravenous administration. It was primarily excreted unchanged in urine, with renal clearance mediated by OAT1/OAT3 and OCT2/MATE1 transporters [3]

γ-GT activity assay: Purified γ-GT enzyme was incubated with γ-glutamyl-p-nitroanilide (substrate) and different concentrations of Dimesna (BNP-7787) at 37°C for 60 minutes. The release of p-nitroaniline was measured spectrophotometrically at 405 nm, and γ-GT inhibition rate was calculated [2]
- Microtubule polymerization assay: Purified tubulin was incubated with paclitaxel or cisplatin in the presence or absence of Dimesna (BNP-7787). Microtubule polymerization dynamics were monitored by measuring turbidity at 340 nm over 60 minutes, and the degree of polymerization/depolymerization was quantified [1]

Renal proximal tubular cell assay: Cells were pretreated with Dimesna (BNP-7787) (0-500 μM) for 2 hours, then exposed to cisplatin (20 μM) for 24 hours. Cell viability was detected by MTT assay; ROS production was measured by fluorescent probe staining; apoptosis was assessed by Annexin V-FITC/PI double staining. Western blot was used to detect γ-GT, apoptotic-related proteins (Bcl-2, Bax, caspase-3) [2]
- Renal transporter cell assay: HEK293 cells overexpressing OAT1, OAT3, OCT2, or MATE1 were incubated with [³H]-labeled Dimesna (BNP-7787) (0-100 μM) for 30 minutes at 37°C. Cell-associated radioactivity was measured by scintillation counting to assess transporter-mediated uptake. Inhibition experiments were performed by co-incubating with specific transporter inhibitors [3]
- Microtubule cell assay: HeLa cells were treated with paclitaxel (10 nM) or cisplatin (50 μM) alone or in combination with Dimesna (BNP-7787) (100-500 μM) for 24 hours. Microtubule structure was visualized by immunofluorescence staining with tubulin-specific antibodies, and morphological changes were observed under a fluorescence microscope [1]

Dissolved in drinking water; 12 or 35 mg/kg ; Oral administration
CP treated Sprague-Dawley rats

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Cisplatin nephrotoxicity model: Male rats were randomly divided into control, cisplatin, and Dimesna (BNP-7787) + cisplatin groups. Dimesna (BNP-7787) was dissolved in normal saline and administered intravenously at 150 mg/kg 30 minutes before cisplatin (7 mg/kg, intravenous injection). Rats were sacrificed 72 hours after cisplatin administration; serum and renal tissues were collected for biochemical and histological analysis [2]
- Bladder tumor prevention model: Female rats were treated with cyclophosphamide (50 mg/kg, intraperitoneal injection) once weekly for 10 weeks. Dimesna (BNP-7787) was dissolved in normal saline and administered intraperitoneally at 100 mg/kg 30 minutes before and 4 hours after each cyclophosphamide injection. Rats were sacrificed 24 weeks after the first cyclophosphamide dose; bladder tissues were collected for tumor incidence analysis and histological examination [4]
- Renal transporter disposition model: Rats were administered [³H]-labeled Dimesna (BNP-7787) (5 mg/kg, intravenous injection). Blood, urine, and kidney tissues were collected at different time points (0-24 hours). Radioactivity in samples was measured by scintillation counting to determine pharmacokinetic parameters and renal excretion efficiency [3]

After intravenous injection of sodium dimethylamine (BNP-7787) into rats, absorption and distribution are rapid, with a plasma half-life (t1/2) of approximately 1.2 hours [3]. It is mainly excreted unchanged in the urine, and approximately 85% of the administered dose is recovered in the urine within 24 hours [3]. Renal clearance is mainly mediated by OAT1/OAT3 (basolateral membrane) and OCT2/MATE1 (apical membrane) transporters, which promote its accumulation in the renal tubules and bladder [3]. Plasma protein binding is <10%, and there is no significant binding to albumin or other plasma proteins [3].

In vitro experiments showed that Dimesna (BNP-7787) at concentrations up to 1000 μM was not cytotoxic to normal kidney cells, HeLa cells, or bladder epithelial cells [1][2][4]. In vivo experiments showed that in animal models, administration of Dimesna (BNP-7787) (at doses up to 500 mg/kg) did not result in significant changes in body weight, organ index, or serum liver and kidney function indicators, indicating low systemic toxicity [2][3][4]. No drug interactions were observed when used in combination with cisplatin, paclitaxel, or cyclophosphamide [1][2][4].

[1]. BNP7787-mediated modulation of paclitaxel- and cisplatin-induced aberrant microtubule protein polymerization in vitro. Mol Cancer Ther. 2010 Sep;9(9):2558-2567.

[2]. Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of gamma-glutamyl transpeptidase. Cancer Chemother Pharmacol. 2010 Apr;65(5):941-951.

[3]. In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna. J Clin Pharmacol. 2012 Apr;52(4):530-542.

[4]. Prevention of urinary bladder tumors in cyclophosphamide-treated rats by additional medication with the uroprotectors sodium 2-mercaptoethane sulfonate (mesna) and disodium 2,2'-dithio-bis-ethane sulfonate (dimesna). Cancer. 1983 Feb 15;51(4):606-609.

Sodium dimethylaminoacetate (DMCA) is a disodium salt of dithioethanesulfonate, a dimer of mesna, and a disulfide bond disruptor (DDA) with urinary tract protection, renal protection, chemoprotection, chemosensitization, and chemoenhancing effects. After administration, DMCA modifies cysteine residues on various proteins, such as kinases EGFR, MET, and ROS1, thereby disrupting extracellular disulfide bonds and modulating the activity of these proteins. This inhibits their signaling pathways and downregulates proliferation signaling in cancer cells that overexpress these kinases. Furthermore, DMCA may enhance the activity of other kinase inhibitors targeting the same proteins. In the kidneys, DMCA is reduced to the free thiol compound mesna, which reacts chemically with the uremic ifosfamide metabolites acrolein and 4-hydroxyifosfamide, thus detoxifying the cytotoxicity. The drug also inhibits cyclophosphamide-induced hemorrhagic cystitis. In addition, DMCA can reduce the toxicity of taxane and platinum-based chemotherapy drugs.

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Dimethylamine sodium (BNP-7787) is a synthetic thiol-containing compound, the disulfide form of mesna. As a chemoprotective agent, it can reduce the toxic effects of chemotherapeutic drugs (cisplatin, cyclophosphamide, paclitaxel) without affecting their antitumor efficacy [1][2][4]
- Its renal protective mechanism involves inhibiting γ-GT-mediated cisplatin activation and scavenging cisplatin-induced reactive oxygen species [2]
- Its urinary protective effect is attributed to its direct binding to cyclophosphamide-derived toxic metabolites in the bladder, thereby preventing mucosal damage and tumorigenesis [4]
- Regulation of microtubule dynamics helps reduce paclitaxel/cisplatin-induced neurotoxicity and myelosuppression [1]

C4H8NA2O6S4

326.34

325.899

16208-51-8

65625

White to off-white solid powder

1.619

0

8

5

16

268

0

S(CCSSCCS(=O)(=O)[O-])(=O)(=O)[O-].[Na+].[Na+]

KQYGMURBTJPBPQ-UHFFFAOYSA-L

InChI=1S/C4H10O6S4.2Na/c5-13(6,7)3-1-11-12-2-4-14(8,9)10;;/h1-4H2,(H,5,6,7)(H,8,9,10);;/q;2*+1/p-2

disodium;2-(2-sulfonatoethyldisulfanyl)ethanesulfonate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)