Cisplatin nephrotoxicity: Inhibition of γ-glutamyl transpeptidase blocks the nephrotoxicity of cisplatin without reducing platinum concentrations in the kidney,☆☆,,★★

Presented as Invited Guest at the Fifty-eighth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Lake Buena Vista, Florida, January 27-30, 1996.
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Abstract

OBJECTIVE: Inhibition of γ-glutamyl transpeptidase activity by acivicin or a large bolus of intravenous glutathione blocks the nephrotoxicity of cisplatin. The purpose of this study was to determine whether these compounds inhibit nephrotoxicity by reducing the amount of platinum retained by the kidney. STUDY DESIGN: The platinum concentration in urine and kidney of cisplatin-treated rats was determined by graphite furnace atomic absorption spectroscopy. Tissues from three experimental groups of rats were analyzed. The first group was treated with a nephrotoxic dose of cisplatin. The second group was treated with acivicin before cisplatin. The third group received a bolus of glutathione before cisplatin. Urine collected for 3 hours after the injection of cisplatin and kidney tissue from animals 5 days after treatment were analyzed for platinum content. RESULTS: Urine from animals pretreated with acivicin had the same concentration of platinum as that of control animals treated with cisplatin alone. Analysis of kidney tissue, blood urea nitrogen and serum creatinine 5 days after treatment showed that pretreatment with acivicin or glutathione blocked the nephrotoxicity of cisplatin. However, these agents did not alter the concentration of platinum in the kidney. CONCLUSIONS: The data in this study reveal that pretreatment with acivicin or glutathione does not block the uptake of platinum into the kidney nor do these agents reduce the concentration of platinum retained by the kidney. The mechanism by which these agents may inhibit the nephrotoxicity of cisplatin is discussed. (Am J Obstet Gynecol 1996;175:270-4.)

Section snippets

Experimental protocol

The treatment protocol has been previously described in detail.3 Briefly, male Sprague-Dawley rats (275 to 300 gm) were lightly anesthetized with methoxyflurane (Metofane, Pitman-Moore, Mundelein, Ill.). A 24-gauge Teflon polytetrafluoroethylene 0.75-inch catheter (Critikon, Tampa, Fla.) was placed in the tail vein. Catheters were capped with intermittent injection caps (Critikon) and flushed with 0.2 ml heparinized saline solution. All solutions were injected through the catheter. The animals

RESULTS

Urine was collected from rats for 3 hours after intravenous injection of 6 mg/kg cisplatin. Platinum concentrations in the urine of acivicin pretreated and control animals is shown in Table I. Animals were injected with an average of 1.8 mg of cisplatin. The animals excreted approximately 30% of the platinum during the first 3 hours. Pretreatment with acivicin to inhibit GGT activity did not affect the amount of platinum excreted. Analysis of the data with a t test showed p > 0.5, which

COMMENT

The mechanism by which cisplatin kills nondividing cells is unclear. Inhibitors of this toxicity may provide insight into this pathway. We analyzed the amount of platinum excreted in the urine during the 3 hours after treatment with cisplatin. Approximately 30% of the platinum was excreted in rats injected with a nephrotoxic dose of cisplatin. Pretreatment of the animals with acivicin to inhibit GGT activity did not change the amount of platinum excreted. These data suggest that inhibition of

Acknowledgements

We thank Mr. James Nicholson from the Trace Metals Laboratory at the University of Virginia and Ms. Mary Katherine Large for their assistance with these studies.

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From the Departments of Cell Biologyaand Obstetrics and Gynecology,bUniversity of Virginia.

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Supported by grant No. R01-CA57530 from the National Cancer Institute, National Institutes of Health.

Reprint requests: Marie H. Hanigan, PhD, Box 439, School of Medicine, University of Virginia, Charlottesville, VA 22908.

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