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Ribonucleotide reductase as a chemotherapeutic target

J G Cory1

  • 1Department of Internal Medicine, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center, Tampa 33612.

Advances in Enzyme Regulation
|January 1, 1988
PubMed

Insights

Targeting ribonucleotide reductase (RR) with combined inhibitors offers a potent strategy for cancer chemotherapy. Inhibiting RR synergistically reduces cancer cell growth and induces cell death by limiting DNA synthesis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Ribonucleotide reductase (RR) is crucial for DNA replication and a viable target for cancer chemotherapy.
  • RR's unique protein subunits and critical role in DNA synthesis present specific therapeutic vulnerabilities.

Purpose of the Study:

  • To investigate the synergistic effects of combining different ribonucleotide reductase inhibitors for cancer treatment.
  • To explore the impact of targeting RR subunits and substrate reduction sensitivities on cancer cell proliferation.

Main Methods:

  • Utilized a combination of RR inhibitors targeting non-heme iron and effector-binding subunits.
  • Assessed the impact of these inhibitors on intracellular dNTP pools and DNA polymerase activity.
  • Evaluated the relationship between DNA synthesis rates and cancer cell viability.

Main Results:

  • Combined RR inhibitors demonstrated synergistic inhibition of cancer cell growth and induced cytotoxicity.
  • Inhibition of RR led to a sigmoidal reduction in DNA polymerase activity due to dNTP pool depletion.
  • Significant decreases in dNTPs resulted in substantial reductions in DNA synthesis and cell replication.

Conclusions:

  • Combined inhibition of ribonucleotide reductase is a promising chemotherapeutic strategy for cancer.
  • The sigmoidal relationship between dNTP levels and DNA synthesis amplifies the cytotoxic effects of RR inhibition.
  • Cancer cell viability is intrinsically linked to maintaining a minimal DNA synthesis rate, making RR inhibition a potent cell death inducer.

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