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Related Experiment Videos

Flow cytometric screening for selective toxicity to multidrug-resistant cells.

O S Frankfurt1

  • 1Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo 14263.

Journal of the National Cancer Institute
|October 1, 1987
PubMed
Summary

Flow cytometry analysis of mixed leukemia cell cultures effectively screens for drugs selectively toxic to multidrug-resistant cells. This method identifies agents that reduce the proportion of resistant P388/R cells, aiding in the development of targeted cancer therapies.

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Area of Science:

  • * Pharmacology
  • * Cell Biology
  • * Cancer Research

Background:

  • * Doxorubicin (DOX) resistance in leukemia poses a significant clinical challenge.
  • * Multidrug-resistant (MDR) cancer cells often exhibit cross-resistance to various chemotherapeutic agents.
  • * Developing rapid screening methods for drugs targeting MDR cells is crucial for effective cancer treatment.

Purpose of the Study:

  • * To evaluate the utility of flow cytometry (FCM) for assessing selective drug toxicity against multidrug-resistant leukemia cells.
  • * To compare the efficacy of doxorubicin, nitrogen mustard (HN2), and x-rays in targeting DOX-resistant P388/R cells versus sensitive P388/S cells.
  • * To establish a reliable assay for screening novel drug candidates for selective MDR cell killing.

Main Methods:

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  • * Mixed cultures of DOX-sensitive (P388/S) and DOX-resistant (P388/R) leukemia cells were treated with drugs or radiation.
  • * Intracellular anthracycline fluorescence measured by FCM distinguished between P388/S and P388/R cell populations.
  • * Changes in the proportion of P388/R cells in mixed cultures served as an indicator of selective toxicity.

    • Main Results:

    • * Doxorubicin selectively eliminated P388/S cells, while nitrogen mustard and x-rays showed selective toxicity towards P388/R cells.
    • * Moderate doses of HN2 and x-rays decreased the proportion of P388/R cells, with high doses eradicating all cells.
    • * Combination treatments (DOX + x-rays, HN2 + x-rays) completely inhibited growth; DOX + HN2 treatment resulted in cultures containing only P388/R cells.
    • * FCM assay detected approximately 1 log greater cell killing of P388/R cells compared to P388/S cells, consistent with colony-formation assays.

    Conclusions:

    • * FCM analysis of mixed leukemia cell cultures is a sensitive and reliable assay for rapidly screening drugs for selective toxicity to multidrug-resistant cells.
    • * This FCM-based method can accelerate the identification of novel therapeutic agents effective against resistant cancers.
    • * The study demonstrates differential drug sensitivity between P388/S and P388/R cells, validating the assay's potential in drug discovery.