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Journal of Veterinary Internal Medicine Jan 2018Transitional cell carcinoma is the most common bladder cancer of dogs. Cisplatin combined with piroxicam provides superior response rates, but unacceptable rates of...
BACKGROUND
Transitional 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/OBJECTIVES
We 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.
ANIMALS
Fourteen client-owned dogs were prospectively enrolled.
METHODS
Tumor 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.
RESULTS
A 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 IMPORTANCE
Tavocept 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.
Topics: Animals; Antineoplastic Agents; Blood Urea Nitrogen; Carcinoma, Transitional Cell; Cisplatin; Creatinine; Diuresis; Dog Diseases; Dogs; Drug Therapy, Combination; Mesna; Piroxicam; Prospective Studies; Renal Insufficiency; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 29080252
DOI: 10.1111/jvim.14848 -
Expert Review of Anticancer Therapy 2016It is important for sarcoma patients to receive the correct dose of Mesna as an adjuvant with ifosfamide to reduce the risk of hemorrhagic cystitis. This paper describes...
INTRODUCTION
It is important for sarcoma patients to receive the correct dose of Mesna as an adjuvant with ifosfamide to reduce the risk of hemorrhagic cystitis. This paper describes a study conducted to evaluate the physicochemical stability of Mesna for injection formulation over 14 days.
METHODS
Mesna samples (n = 4, 20 mg/ml) were incubated in glass vials at 37 + 0.5ºC. Mesna concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS), and nuclear magnetic resonance spectroscopy (NMR) was used to detect degradation products. Evaporative losses and pH were also monitored.
RESULTS
Our results differed from those published in existing literature. Both LC-MS/MS and NMR indicated that Mesna was unstable. The mean percentage decrease in Mesna concentration was 40% by day 14 of the analysis. The presence of Mesna's dimer Dimesna was detected on day 0 and its concentration increased over time. Dimesna was the only by-product identified.
CONCLUSION
Both LC-MS/MS and NMR analyses confirmed the instability of Mesna and its conversion into Dimesna.
Topics: Chromatography, Liquid; Drug Stability; Drug Storage; Hydrogen-Ion Concentration; Injections; Magnetic Resonance Spectroscopy; Mesna; Tandem Mass Spectrometry
PubMed: 26568378
DOI: 10.1586/14737140.2016.1121106 -
Molecules (Basel, Switzerland) Mar 2015Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth...
Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the development and/or progression of human diseases. Grx and Prx are overexpressed in human cancers, including human lung cancers. BNP7787 is a novel investigational agent that has been evaluated in previous clinical studies, including non-small cell lung cancer (NSCLC) studies. Herein, data from activity assays, mass spectrometry analyses, and X-ray crystallographic studies indicate that BNP7787 forms mixed disulfides with select cysteine residues on Grx and Prx and modulates their function. Studies of interactions between BNP7787 and Trx have been conducted and reported separately. Despite the fact that Trx, Grx, and Prx are functionally distinct proteins that impact oxidative stress, cell proliferation and disease processes through different intracellular pathways, BNP7787 can modify each protein and appears to modulate function through mechanisms that are unique to each target protein. Tumor cells are often genomically heterogeneous containing subpopulations of cancer cells that often express different tumor-promoting proteins or that have multiple dysregulated signaling pathways modulating cell proliferation and drug resistance. A multi-targeted agent that simultaneously modulates activity of proteins important in mediating cell proliferation by functionally distinct intracellular pathways could have many potentially useful therapeutic applications.
Topics: Antineoplastic Agents; Binding Sites; Crystallography, X-Ray; Cysteine; Glutaredoxins; Homeodomain Proteins; Humans; Mass Spectrometry; Mesna; Models, Molecular; Peroxiredoxins; Protein Structure, Tertiary
PubMed: 25793542
DOI: 10.3390/molecules20034928 -
Amino Acids Mar 2015The chemical reduction of the disulfide homodimer dimesna to its constituent mesna moieties is essential for its mitigation of nephrotoxicity associated with cisplatin...
The chemical reduction of the disulfide homodimer dimesna to its constituent mesna moieties is essential for its mitigation of nephrotoxicity associated with cisplatin and ifosfamide anticancer therapies and enhancement of dialytic clearance of the cardiovascular risk factor homocysteine. The objective of this study was to investigate potential enzymatic and non-enzymatic mechanisms of intracellular dimesna reduction. Similar to endogenous intracellular disulfides, dimesna undergoes thiol-disulfide exchange with thiolate anion-forming sulfhydryl groups via the two-step SN2 reaction. Determination of equilibrium constants of dimesna reduction when mixed with cysteine or glutathione provided a mechanistic explanation for dramatic cysteine and homocysteine depletion, but sparing of the endogenous antioxidant glutathione, previously observed during mesna therapy. Dimesna was reduced by recombinant enzymes of the thioredoxin system; however, oxidation of NADPH by the glutaredoxin system was only observed in the presence of combined dimesna and reduced glutathione, suggesting formation of oxidized glutathione following an initial non-enzymatic reduction of dimesna. Production of mesna by enzymatic and non-enzymatic mechanisms in HeLa cell lysate following dimesna incubation was demonstrated by a loss in mesna production following protein denaturation and prediction of residual non-enzymatic mesna production by mathematical modeling of thiol-disulfide exchange reactions. Reaction modeling also revealed that mixed disulfides make up a significant proportion of intracellular thiols, supporting their role in providing additional nephroprotection, independent of direct platinum conjugation.
Topics: Animals; Cell Line; Cysteine; Female; Glutathione; Homocysteine; Humans; Kidney; Liver; Mesna; Mice; Oxidation-Reduction
PubMed: 25488427
DOI: 10.1007/s00726-014-1882-0