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Related Experiment Videos

Platinate toxicity: past, present, and prospects.

A M Guarino, D S Miller, S T Arnold

    Cancer Treatment Reports
    |September 1, 1979
    PubMed
    Summary

    This study evaluated animal models and in vitro methods to predict cis-diamminedichloroplatinum(II) toxicity. Rat and dog models were most predictive, while an in vitro flounder tubule system offered a faster, cheaper alternative for assessing nephrotoxicity.

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    Area of Science:

    • Toxicology
    • Pharmacology
    • Biochemistry

    Background:

    • Cis-diamminedichloroplatinum(II) is a widely used chemotherapy drug.
    • Understanding its toxicity is crucial for patient safety and drug development.
    • Predictive models are needed to assess platinum-based drug toxicity.

    Purpose of the Study:

    • To evaluate the predictive value of different animal models for cis-diamminedichloroplatinum(II) toxicity.
    • To identify less nephrotoxic analogs of cis-diamminedichloroplatinum(II).
    • To develop and validate a rapid in vitro renal toxicity screen.

    Main Methods:

    • Comparative toxicologic assessment in mouse, monkey, rat, and dog models.
    • In vivo nephrotoxicity studies in rats using cis-diamminedichloroplatinum(II) and analogs.

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  • In vitro renal toxicity screening using isolated flounder tubules.
  • Biochemical analysis to identify the molecular targets of platinum compounds.

    • Main Results:

    • Rat and dog models demonstrated the highest predictive accuracy for cis-diamminedichloroplatinum(II) toxicity.
    • Eight tested analogs were found to be less nephrotoxic than cis-diamminedichloroplatinum(II) in the rat model.
    • The in vitro flounder tubule system identified approximately half of the 26 tested compounds as less toxic than the parent compound.
    • In vitro studies indicated that platinum compounds inhibit ATPases, suggesting a unified mechanism of toxicity.

    Conclusions:

    • Rodent and canine models are valuable for predicting cis-diamminedichloroplatinum(II) toxicity.
    • An in vitro renal toxicity screen using flounder tubules is a rapid, cost-effective alternative to in vivo models.
    • Inhibition of ATPases is a likely mechanism underlying the toxicity of platinum compounds across various organs.