Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil

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Chemotherapy-induced Vascular Toxicity - Real-time In vivo Imaging of Vessel Impairment
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B W Futscher1, K Campbell, W S Dalton

  • 1Arizona Cancer Center, University of Arizona, Tucson 85724.

Cancer Research
|September 15, 1992
PubMed

Insights

Drug-resistant myeloma cells showed increased sensitivity to nitrosoureas like streptozotocin (STZ) and BCNU when P-glycoprotein was inhibited. This sensitivity resulted from the loss of DNA repair enzyme O6-Methylguanine DNA methyltransferase (MGMT).

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Multiple myeloma is a cancer of plasma cells.
  • Drug resistance is a major challenge in multiple myeloma treatment.
  • Nitrosoureas (streptozotocin [STZ], BCNU) are chemotherapy agents.
  • P-glycoprotein is a key factor in multidrug resistance.

Purpose of the Study:

  • To investigate the effects of STZ and BCNU on drug-resistant multiple myeloma cells.
  • To understand the role of P-glycoprotein and O6-Methylguanine DNA methyltransferase (MGMT) in drug resistance and sensitivity.

Main Methods:

  • Cultured human multiple myeloma cell line RPMI 8226 and its drug-resistant variants.
  • Selected for resistance to doxorubicin (DOX) alone and in combination with verapamil.
  • Assessed cytotoxicity of STZ and BCNU on these cell lines.
  • Investigated the expression and function of MGMT.

Main Results:

  • DOX-resistant cells showed similar STZ/BCNU sensitivity as parent cells.
  • Cells selected with DOX plus verapamil (P-glycoprotein inhibitor) exhibited collateral sensitivity to STZ and BCNU.
  • This collateral sensitivity was linked to functional loss of MGMT due to decreased gene expression.
  • MGMT gene expression loss was not due to mutations in the coding region.

Conclusions:

  • Inhibition of P-glycoprotein can lead to collateral sensitivity to nitrosoureas in drug-resistant myeloma.
  • Loss of MGMT expression and function is responsible for this collateral sensitivity.
  • These findings suggest potential new therapeutic strategies for multiple myeloma.
  • Developed cell lines serve as models for studying MGMT expression mechanisms.

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