Accumulation of BNP7787 in Human Renal Proximal Tubule Cells

Hausheer, Frederick H.; Ding, Desheng; Shanmugarajah, Dakshine; Leverett, Betsy D.; Huang, Quili; Chen, X.; Kochat, Harry; Ayala, Philippe Y.; Petluru, Pavankumar N.; Parker, Aulma R.

doi:10.1002/jps.22510

Cited by 5 publications

(6 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, it was reported that BNP7787 does not interfere in the antitumor activity of cisplatin in human ovarian cancer cell lines in vitro or in nude mice bearing human ovarian cancer xenografts (Boven et al 2002). The drug is currently undergoing global Phase III studies (Hausheer et al 2011a). …”

Section: The Antitumor Mechanism Versus the Nephrotoxic Mechanismmentioning

confidence: 97%

“…BNP7787 is selectively taken up by the kidneys where it is converted into mesna (Ormstad and Uehara 1982). BNP7787 may accumulate in renal tubular cells, where it can exert its protective effects against cisplatin-induced nephrotoxicity by direct covalent conjugation of mesna with cisplatin (Hausheer et al 2011a). Besides the formation of this inactive adduct with cisplatin, other mechanisms might be involved in the protection: (a) inhibition of GGT, (b) inhibition of AP-N, and (c) inhibition of C-S lyase (Hausheer et al 2010(Hausheer et al , 2011b.…”

Section: The Antitumor Mechanism Versus the Nephrotoxic Mechanismmentioning

confidence: 99%

See 1 more Smart Citation

Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update

et al. 2012

View full text Add to dashboard Cite

Section: The Antitumor Mechanism Versus the Nephrotoxic Mechanismmentioning

confidence: 97%

Section: The Antitumor Mechanism Versus the Nephrotoxic Mechanismmentioning

confidence: 99%

Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update

et al. 2012

View full text Add to dashboard Cite

“…Since the active form of NAMI-A is the Ru(II) form, co-injection of MESNA with NAMI-A does not deactivate NAMI-A. The product of oxidation of MESNA, the dimeric form, BNP7787™, 43,63,64 has been evaluated as a much better nephroprotectant than MESNA itself. 65…”

Section: Rsh ð Rsmentioning

confidence: 99%

Kinetics and mechanistic investigation into the possible activation of imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(iii)], NAMI-A, by 2-mercaptoethane sulfonate

et al. 2014

View full text Add to dashboard Cite

Imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(III)], NAMI-A, is a promising antimetastatic prodrug with high specificity for metastatic cancer cells. Limited activity of NAMI-A against primary tumor suggests that its use in combination with other anticancer drug(s) might present a more desirable therapeutic outcome. The mechanism of activation and action of this prodrug is still largely unknown. The biological targets, as well, have not yet been delineated. The kinetics and mechanism of interaction of NAMI-A with 2-mercaptoethane sulfonate, MESNA, a chemoprotectant, have been studied spectrophotometrically under pseudo-first order conditions of excess MESNA. The reaction is characterized by initial reduction of NAMI-A and formation of dimeric MESNA as evidenced by electospray ionization mass spectrometry. A first order dependence on both NAMI-A and MESNA was obtained and a bimolecular rate constant of 0.71 ± 0.06 M(-1) s(-1) was deduced. Activation parameters determined (ΔS(≠) = -178.12 ± 0.28 J K(-1) mol(-1), ΔH(≠) = 20.64 ± 0.082 kJ mol(-1) and ΔG(≠) = 75.89 ± 1.76 kJ mol(-1) at 37 ± 0.1 °C and pH 7.4) are indicative of formation of an associative intermediate prior to product formation and subsequent hydrolysis of the reduced complex. Our results suggest that MESNA might be able to activate the prodrug while still protecting against toxicity when given in a regimen involving NAMI-A and chemotherapy drug(s) that induce bladder and kidney toxicities.

show abstract

“…Tavocept (BNP7787; disodium 2,2′‐dithio‐bis‐ethane sulfonate) is a water‐soluble disulfide form of mesna under investigation as a chemoprotectant . Tavocept is converted to mesna in the kidneys, which then locally inactivates the toxic platinum species . In preclinical studies, Tavocept protected against cisplatin nephrotoxicity in both rats and dogs, and the use of Tavocept before cisplatin in people allows a 75% decrease in fluid diuresis .…”

mentioning

confidence: 99%

“…[22][23][24] Tavocept is converted to mesna in the kidneys, which then locally inactivates the toxic platinum species. 25 In preclinical studies, Tavocept protected against cisplatin nephrotoxicity in both rats and dogs, and the use of Tavocept before cisplatin in people allows a 75% decrease in fluid diuresis. [26][27][28] A similar decrease in fluid diuresis volume requirements would be ideal for dogs at risk of volume overload using the standard cisplatin administration protocol.…”

mentioning

confidence: 99%

Clinical Evaluation of Tavocept to Decrease Diuresis Time and Volume in Dogs with Bladder Cancer Receiving Cisplatin

Henry

Flesner

Axiak‐Bechtel

et al. 2017

Veterinary Internal Medicne

View full text Add to dashboard Cite

BackgroundTransitional cell carcinoma is the most common bladder cancer of dogs. Cisplatin combined with piroxicam provides superior response rates, but unacceptable rates of nephrotoxicity. Tavocept is a chemoprotectant that has mitigated cisplatin toxicity and decreased the required infusion/diuresis volume in clinical trials in humans.Hypothesis/ObjectivesWe hypothesized that Tavocept would decrease diuresis volume and time and facilitate safe administration of a cisplatin/piroxicam protocol to dogs with bladder cancer. Secondary objectives were to compare response rate and survival times to an historical comparator group treated without Tavocept.AnimalsFourteen client‐owned dogs were prospectively enrolled.MethodsTumor volume was measured by computed tomography at days 0, 42, and 84. Dogs received combination Tavocept/cisplatin with a shortened diuresis protocol. A total of 4 doses was planned, with concurrent administration of piroxicam. Serial biochemical analyses were evaluated for azotemia.ResultsA 90‐minute infusion/diuresis time was used for all dogs. Three dogs (21%) had concurrent increases in serum creatinine (>2.0 mg/dL) and BUN (>42 mg/dL) concentrations; 2 of these dogs were isosthenuric. This frequency of nephrotoxicity is significantly less (P = 0.0406) than that of an historical control group treated without Tavocept. Overall response rate was 27%. Median survival time was comparable to historical controls (253 vs. 246 days).Conclusions and Clinical ImportanceTavocept decreased the required diuresis time with cisplatin from > 6 hours to 90 minutes, while also decreasing occurrence of azotemia. Survival time was comparable, but the response rate was inferior to an historical comparator group. Further evaluation in other tumors susceptible to platinum agents is warranted.

show abstract

Accumulation of BNP7787 in Human Renal Proximal Tubule Cells

Cited by 5 publications

References 30 publications

Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update

Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update

Kinetics and mechanistic investigation into the possible activation of imidazolium trans-[tetrachloridodimethylsulfoxideimidazoleruthenate(iii)], NAMI-A, by 2-mercaptoethane sulfonate

Clinical Evaluation of Tavocept to Decrease Diuresis Time and Volume in Dogs with Bladder Cancer Receiving Cisplatin

Contact Info

Product

Resources

About