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What makes tumors multidrug resistant?

Piet Borst1, Jos Jonkers, Sven Rottenberg

  • 1The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands. p.borst@nki.nl

Cell Cycle (Georgetown, Tex.)
|November 14, 2007
PubMed

Insights

Genetically modified mouse models with spontaneous tumors offer new insights into drug resistance mechanisms. These models show resistance develops via drug transporters, not apoptosis interference, and can aid in developing new cancer treatments.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Spontaneous tumors in genetically modified mice mimic human cancers.
  • Studying drug resistance mechanisms in these models is crucial for therapeutic development.

Purpose of the Study:

  • To investigate drug resistance mechanisms in mouse mammary tumors induced by Brca1 and p53 deletion.
  • To evaluate the potential of these models for drug development and treatment regimen improvement.

Main Methods:

  • Induction of mammary tumors via conditional deletion of Brca1 and p53 in mice.
  • Treatment of tumors with doxorubicin, docetaxel, and cisplatin to assess response and resistance development.
  • Analysis of resistance mechanisms, focusing on drug transporters and apoptosis/senescence pathways.

Main Results:

  • Tumors responded to doxorubicin and docetaxel but developed resistance, primarily through drug transporter upregulation.
  • Cisplatin treatment led to tumor response without resistance development, even after repeated doses.
  • Resistance mediated by interference with apoptosis or senescence pathways was not observed in these tumors.

Conclusions:

  • Drug resistance in these models is mainly mediated by drug transporters, not cell death pathway interference.
  • Spontaneous mouse tumor models are valuable tools for studying drug resistance and advancing cancer therapy.
  • The resistant remnant fraction in these models may serve as a platform for testing the tumor stem cell hypothesis.

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