Controversial role of Gamma-Glutamyl Transferase activity in cisplatin nephrotoxicity

Fliedl, Lukas

doi:10.14573/altex.1311152

Cited by 16 publications

(8 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, more recent studies propose a different view. Fliedl et al [ 28 ] found that after inhibiting GGT expression through a specific inhibitor, the renal toxicity of cisplatin decreased. These findings are indicative of a relationship between cisplatin nephrotoxicity and GGT-mediated drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

The Predictive Value of Pre-therapeutic Serum Gamma-glutamyl transferase in Efficacy and Adverse Reactions to Neoadjuvant Chemotherapy among Breast Cancer Patients

Sun

Yin

et al. 2020

J Breast Cancer

View full text Add to dashboard Cite

Purpose Gamma-glutamyl transferase (GGT) has been reported as being involved in tumor progression. Previous studies documented a potential relationship between serum GGT level and survival outcome in several types of human malignancies. However, the association between serum GGT levels and response to neoadjuvant chemotherapy (NAC) has not yet been reported. The present study aimed to evaluate the association between pre-therapeutic serum GGT level and the efficacy, long-term survival, and adverse reactions of NAC and to investigate its role in predicting NAC sensitivity in patients with breast cancer. Methods A total of 129 patients were recruited and stratified into 2 groups according to serum GGT level (< 29 U/L and ≥ 29 U/L). The association between pre-therapeutic serum GGT levels and clinicopathological parameters was examined. The correlation between pre-therapeutic serum GGT levels and pathological complete response (pCR) was analyzed using univariate and multivariate logistic regression. Survival analyses of relapse-free survival (RFS) and disease-free survival (DFS) were performed. Pearson's χ 2 test and multivariate logistic regression model were used to analyze the correlation between pre-therapeutic serum GGT levels and adverse reactions. Results Pre-therapeutic serum GGT levels were associated with pCR among breast cancer patients treated with NAC. Multivariate analysis showed that low-level GGT significantly increased pCR rate. Patients in the high-level GGT group had poorer survival than those in the low-level GGT group. Subgroup analysis demonstrated that serum GGT level was potentially related to RFS and DFS in the hormone receptor-positive group. Low levels of GGT are significantly associated with a higher incidence of neutropenia. Conclusion Pre-therapeutic serum GGT level is an independent and novel biomarker for predicting the efficiency, prognosis, and adverse reactions to NAC in breast cancer patients. Patients with low pre-therapeutic serum GGT levels are more likely to have higher pCR rates, better RFS and DFS, and higher hematologic toxicity. Trial Registration ClinicalTrials.gov Identifier: NCT02199418 , NCT02221999

show abstract

Section: Discussionmentioning

confidence: 99%

The Predictive Value of Pre-therapeutic Serum Gamma-glutamyl transferase in Efficacy and Adverse Reactions to Neoadjuvant Chemotherapy among Breast Cancer Patients

Sun

Yin

et al. 2020

J Breast Cancer

View full text Add to dashboard Cite

show abstract

“…They are further metabolized to a reactive thiol group which is highly nephrotoxic [68]. The fact that GGT is predominantly found at the apical surface of the proximal tubule’s epithelial cells make it a desirable and possible target for managing cisplatin associated nephrotoxicity [72].…”

Section: Cisplatin-induced Nephrotoxicitymentioning

confidence: 99%

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

Tănase

Gosav

Radu

et al. 2019

IJMS

116

View full text Add to dashboard Cite

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

show abstract

“…However, deletion of organic anion transporters or the endocytic receptor megalin also attenuates cisplatin toxicity in mouse models 38,155 , suggesting that alternative modes of cisplatin uptake exist. Cisplatin is also a substrate for γ-glutamyltransferase (GGT), which is expressed by proximal tubules, but conflicting reports exist as to whether GGT processing attenuates or exacerbates cisplatin toxicity 63 . Cisplatin also shows general cytotoxicity at high doses, suggesting that nonspecific toxicity responses are possible.…”

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

“…These renal enzymes, especially CYP3A4 and CYP3A5 and UGT1A9 and UGT2B7, might facilitate drug detoxification and efflux 10,58,59 , which could lead to drug–drug interactions because substrates that inhibit these enzymes could cause other drugs to accumulate in the proximal tubule, thereby exacerbating their nephrotoxic effects 60 . In addition to their detoxifying effects, various studies have demonstrated that these enzymes can also bioactivate xenobiotics, potentially exacerbating their nephrotoxic effects 61–63 . However, the degree to which renal biotransformation contributes to the nephrotoxic effects of pharmaceutical compounds in vivo is not yet clear.…”

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

View full text Add to dashboard Cite

In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

show abstract

Controversial role of Gamma-Glutamyl Transferase activity in cisplatin nephrotoxicity

Abstract: Summary Nephrotoxicity of chemotherapeutics is a major hindrance in the treatment

Cited by 16 publications

References 48 publications

The Predictive Value of Pre-therapeutic Serum Gamma-glutamyl transferase in Efficacy and Adverse Reactions to Neoadjuvant Chemotherapy among Breast Cancer Patients

The Predictive Value of Pre-therapeutic Serum Gamma-glutamyl transferase in Efficacy and Adverse Reactions to Neoadjuvant Chemotherapy among Breast Cancer Patients

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

Advances in predictive in vitro models of drug-induced nephrotoxicity

Contact Info

Product

Resources

About