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Platinum-Based Drugs in Cancer Therapy pp 89–113Cite as

Cisplatin Accumulation

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Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Accumulation of a drug is the net effect of drug influx and efflux. Since the first reports of accumulation defects in cells with acquired resistance to cisplatin (1), much effort has been directed toward defining the mechanisms by which cisplatin enters and leaves cells. These mechanisms have been difficult to pinpoint. Several reviews of the literature on cisplatin accumulation have been previously published that document the evidence supporting either passive diffusion or carrier-mediated transport as the dominant mechanism of cisplatin influx (1–5). A definitive case for carrier-mediated transport cannot be made since accumulation is not saturable nor inhibitable with structural analogs (6–11). Likewise, studies demonstrating directly that intact resistant cells have enhanced efflux, presumably via a carrier, are scarce. Conversely, a wide variety of physiologic conditions and pharmacologic treatments modulate cisplatin accumulation, which suggests that a regulatable carrier or channel is an important determinant of cisplatin entry into cells. For example, accumulation is partially Na+dependent and can be altered by adenosine triphosphate (ATP) depletion, cyclic adenosine monophosphate (cAMP) elevation, protein kinase C agonists, osmotic strength, pH, membrane polarization, calmodulin antagonists, This article is not an official Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the FDA is intended or should be inferred.

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  1. Paul A. Andrews
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  1. CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, UK

    Lloyd R. Kelland

  2. Department of Chemistry, Virginia Commonwealth University, USA

    Nicholas P. Farrell

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Andrews, P.A. (2000). Cisplatin Accumulation. In: Kelland, L.R., Farrell, N.P. (eds) Platinum-Based Drugs in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-012-4_4

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  • DOI: https://doi.org/10.1007/978-1-59259-012-4_4

  • Publisher Name: Humana Press, Totowa, NJ

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