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Ribonucleotide reductase inhibitors: a new look at an old target for radiosensitization
Tobias R Chapman1, Timothy J Kinsella
1Tufts University School of Medicine Boston, MA, USA.
Abstract:
Ribonucleotide reductase (RR), the rate limiting enzyme in the synthesis and repair of DNA, has been studied as a target for inhibition in the treatment of cancer for many years. While some researchers have focused on RR inhibitors as chemotherapeutic agents, particularly in hematologic malignancies, some of the most promising data has been generated in the field of radiosensitization. Early pre-clinical studies demonstrated that the addition of the first of these drugs, hydroxyurea, to ionizing radiation (IR) produced a synergistic effect in vitro, leading to a large number of clinical studies in the 1970-1980s. These studies, mainly in cervical cancer, initially produced a great deal of interest, leading to the incorporation of hydroxyurea in the treatment protocols of many institutions. However, over time, the conclusions from these studies have been called into question and hydroxyurea has been replaced in the standard of care of cervical cancer. Over the last 10 years, a number of well-done pre-clinical studies have greatly advanced our understanding of RR as a target. Those advances include the elucidation of the role of p53R2 and our understanding of the temporal relationship between the delivery of IR and the response of RR. At the same time, new inhibitors with increased potency and improved binding characteristics have been discovered, and pre-clinical and early clinical data look promising. Here we present a comprehensive review of the pre-clinical and clinical data in the field to date and provide some discussion of future areas of research.
Insights
Ribonucleotide reductase (RR) inhibition shows promise in cancer radiosensitization. Recent advances in understanding RR, including p53R2, and new potent inhibitors offer renewed hope for cancer treatment strategies.
Area of Science:
- Biochemistry
- Oncology
- Radiotherapy
Background:
- Ribonucleotide reductase (RR) is a key enzyme in DNA synthesis and repair, making it a long-standing target for cancer therapy.
- While initially explored as a chemotherapeutic, RR inhibitors have shown significant potential in radiosensitization, particularly with ionizing radiation (IR).
- Early studies with hydroxyurea demonstrated synergistic effects with IR, leading to widespread clinical investigation, though its role has since been re-evaluated.
Purpose of the Study:
- To comprehensively review the pre-clinical and clinical data on Ribonucleotide reductase (RR) inhibition in cancer treatment.
- To elucidate the recent advancements in understanding RR's role, including the p53R2 protein and its temporal relationship with IR.
- To discuss the development of novel, more potent RR inhibitors and their potential in future cancer therapies.
Main Methods:
- Review of pre-clinical studies on RR inhibitors and radiosensitization.
- Analysis of historical and recent clinical trial data involving RR inhibitors and IR.
- Examination of molecular mechanisms, including the role of p53R2 and IR timing.
Main Results:
- Early clinical studies with hydroxyurea showed promise but yielded controversial conclusions, leading to its removal from standard cervical cancer care.
- Recent pre-clinical research has significantly advanced the understanding of RR's function and its interaction with IR.
- New RR inhibitors with enhanced potency and binding affinity have been developed, showing promising pre-clinical and early clinical results.
Conclusions:
- Ribonucleotide reductase (RR) remains a compelling target for cancer treatment, especially in combination with radiotherapy.
- Advances in understanding RR biology and the development of novel inhibitors warrant further investigation.
- Future research should focus on optimizing RR-targeted therapies and their integration into clinical practice for improved cancer outcomes.
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