Paper
Reduction of the drug-induced nephrotoxicity by ATP-MgCl2. 1. Effects on the cis-Diamminedichloroplatinum-treated isolated perfused kidneys

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Abstract

cis-Diamminedichloroplatinum (CDDP), a widely used cancer chemotherapeutic agent, has been shown to cause dose-dependent acute renal failure (ARF) probably secondary to a direct nephrotoxic effect on proximal tubule cells. The aim of this study was to determine whether administration of ATP-MgCl2 could ameliorate the deleterious effects of CDDP. Isolated rat kidneys were perfused for 2 hr with a 3.5 g % dextran T-110-Krebs HCO3 solution containing 100 μg/ml of CDDP. [3H]Inulin was added to measure GFR. Trace amounts of 14C-methylated cytochrome c (cyt) were added to the perfusate to determine the protein reabsorptive capacity (a sensitive indicator of tubular damage) of isolated perfused rat kidneys. Cyt, inulin radioactivity, and [Na+] were measured in the perfusate and urine in control and CDDP-treated kidneys. In additional experiments, ATP-MgCl2 was added simultaneously (0.3 mM) or 1 hr (2 mM) after CDDP treatment. The results indicate that after 2 hr of perfusion, CDDP treatment led to a marked inhibition of protein reabsorption with only a minimal decrease in Na+ and H2O absorption. Furthermore, GFR was not significantly altered despite a marked diuresis. Post-treatment with ATP-MgCl2 led to partial alleviation of the nephrotoxic effect of CDDP after 1 hr of perfusion. ATP-MgCl2 treatment simultaneously with CDDP, however, fully protected the protein reabsorptive capacity of CDDP-treated kidneys. The potential for administering ATP-MgCl2 simultaneously with CDDP suggests a new therapeutic modality in preventing ARF due to CDDP therapy.

References (47)

  • M.G. Clemens et al.

    Hepatic microvascular protection from ischemia with ATP-MgCl2

    Microvasc. Res.

    (1983)
  • Z.A. Cohn

    The regulation of pinocytosis in mouse macrophages. I. Metabolic requirements as defined by the use of inhibitors

    J. Exp. Med.

    (1966)
  • G. DeMello et al.

    Nephron function of the isolated perfused rat kidney

    Amer. J. Physiol.

    (1976)
  • M. Dentino et al.

    Long term effects of cis-diamminedichloroplatinum (DDP) on renal function and structure in man

    Cancer

    (1978)
  • D.C. Dobyan et al.

    Mechanism of cis-platinum nephrotoxicity. II. Morphologic observations

    J. Pharm. Exp. Ther.

    (1980)
  • R.G. Evans et al.

    Intravascular passage of adenosine triphosphate through lung of baboon

    J. Physiol.

    (1978)
  • J. Filipski et al.

    Thiourea reverses cross-links and restores biological activity in DNA treated with dichlorodiammineplatinum (II)

    Science (Washington, D. C.)

    (1979)
  • K.M. Gaudio et al.

    Accelerated cellular recovery after an ischemic renal injury

    Amer. J. Pathol.

    (1983)
  • R.S. Goldstein et al.

    Cis-dichlorodiammineplatinum nephrotoxicity

  • J.C. Gonzalez-Vitale et al.

    The renal pathology in clinical trials of cis-diamminedichlorideplatinum (II)

    Cancer

    (1977)
  • A.M. Guarino et al.

    Platinum toxicity: Past, present and prospects

    Cancer Treat. Rep.

    (1979)
  • H. Hirasawa et al.

    Reversal of ischemic induced hepatic cellular edema by administration of ATP-MgCl2

    Surg. Forum

    (1980)
  • S.B. Howell et al.

    Effect of sodium thiosulfate on cis-dichlorodiammineplatinum (II) toxicity and anti-tumor activity in L1210 leukemia

    Cancer Treat. Rep.

    (1980)
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