ABSTRACT
Cisplatin is an anticancer agent that induces renal proximal tubule lesions in many species. Studies were conducted in Sprague-Dawley and Han-Wistar rats to evaluate the utility of novel preclinical biomarkers of nephrotoxicity for renal lesions caused by this compound. Groups of 10 males of each strain were given a single intraperitoneal injection of 0.3, 1, or 3 mg/kg cisplatin and were sacrificed on days 2, 3, and 5. The novel biomarkers α-glutathione-S-transferase (α-GST) (for proximal tubular injury), µ-glutathione-S-transferase (µ-GST) (for distal tubular injury), clusterin (for general kidney injury), and renal papillary antigen-1 (RPA-1) (for collecting duct injury) were measured in urine by enzyme immunoassay. Histologically, degeneration and necrosis of the S3 segment of the renal proximal tubule were observed on day 2 (Han-Wistar) and days 3 and 5 (both strains) at 1 and 3 mg/kg. Results showed that in both strains of rats, urinary α-GST and clusterin can be detected in urine soon after injury, are more sensitive than BUN and serum creatinine, and therefore are usable as noninvasive biomarkers of proximal tubule injury. Changes in both µ-GST or RPA-1 were considered to represent secondary minor effects of proximal tubular injury on distal segments of the nephron.
Subject(s)
Antineoplastic Agents/toxicity , Biomarkers/metabolism , Cisplatin/toxicity , Kidney Diseases/diagnosis , Animals , Clusterin/metabolism , Glutathione Transferase/metabolism , Kidney Diseases/chemically induced , Kidney Diseases/metabolism , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Male , Rats , Rats, Sprague-Dawley , Rats, Wistar , Reproducibility of Results , Species Specificity , Specific Pathogen-Free OrganismsABSTRACT
Application of any new biomarker to support safety-related decisions during regulated phases of drug development requires provision of a substantial data set that critically assesses analytical and biological performance of that biomarker. Such an approach enables stakeholders from industry and regulatory bodies to objectively evaluate whether superior standards of performance have been met and whether specific claims of fit-for-purpose use are supported. It is therefore important during the biomarker evaluation process that stakeholders seek agreement on which critical experiments are needed to test that a biomarker meets specific performance claims, how new biomarker and traditional comparators will be measured and how the resulting data will be merged, analyzed and interpreted.
Subject(s)
Biomarkers , Drug Discovery , Pharmaceutical Preparations , Animals , Drug Discovery/legislation & jurisprudence , Drug Discovery/methods , Drug-Related Side Effects and Adverse Reactions , Humans , Pharmaceutical Preparations/standardsABSTRACT
Protozoal parasites of the genus Leishmania are transmitted to their vertebrate host within the saliva of the sand fly during a blood meal. The saliva of the sand fly Lutzomyia longipalpis contains maxadilan, a potent vasodilator and immunomodulator. Maxadilan has been shown to enhance the virulence of L. major in all strains of laboratory mice when injected along with the organism. Increased haematopoiesis has been associated with enhanced susceptibility to Leishmania organisms. Here, we show that maxadilan alone stimulates bone marrow haematopoiesis through its ability to stimulate interleukin-6 production by bone marrow stromal cells. Moreover, these effects of maxadilan are mediated through the interaction of maxadilan with the pituitary adenylate cyclase activating polypeptide receptor. These data suggest that increasing haematopoiesis may be yet another way that maxadilan enhances susceptibility of mice to Leishmania infection.
