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Elevated Ribonucleotide Reductase Levels Associate With Suppressed Radiochemotherapy Response in Human Cervical Cancers
  1. Charles A. Kunos, MD, PhD*,
  2. Tomas Radivoyevitch, PhD,
  3. Adam Kresak, BS,
  4. Dawn Dawson, MD,
  5. James Jacobberger, PhD§,
  6. Bin Yang, MD, PhD and
  7. Fadi W. Abdul-Karim, MD
  1. *Departments of Radiation Oncology,
  2. Epidemiology and Biostatistics,
  3. Pathology,
  4. §General Medicine, CASE Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH; and
  5. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH.
  1. Address correspondence and reprint requests to Charles Kunos, MD, PhD, Department of Radiation Oncology, University Hospitals of Cleveland, 11100 Euclid Ave, LTR 6068, Cleveland, OH 44106. E-mail: charles.kunos@UHhospitals.org.

Abstract

Objective Ribonucleotide reductase (RNR) supplies deoxyribonucleotide diphosphates demanded by cells to repair radiation-induced DNA damage. Here, we investigate the impact of pretherapy RNR M1, M2, and M2b (p53R3) subunit level upon human cervical cancer radiochemosensitivity.

Materials/Methods Immunohistochemistry was performed on a tissue array comprised of 18 paired benign uterine cervix and stage IB2 cervical cancers to evaluate the relationship between cytosolic RNR M1, M2, and M2b staining intensity and radiochemotherapy cancer response. Patients underwent surgical hysterectomy (n = 8), or daily radiation (45 Gy), coadministered once-weekly cisplatin (40 mg/m2), then low–dose rate brachytherapy (30 Gy) followed by adjuvant hysterectomy (n = 10). Radiochemotherapy response was determined by Response Evaluation Criteria In Solid Tumors version 1.0 criteria during brachytherapy. Cancer relapse rates and disease-free survival were calculated.

Results M1, M2, and M2b antibody staining intensity was low (0–1+) in benign uterine cervical tissue. M1 and M2b immunoreactivity was 2+ or 3+ in most (13/18) cervical cancers. M2 immunoreactivity was 3+ in nearly all (16/18) cervical cancers. Cervical cancers overexpressing M1 and M2b had an increased hazard for incomplete radiochemotherapy response, relapse, and shortened disease-free survival.

Conclusions Ribonucleotide reductase subunit levels may predict human cervical cancer radiochemosensitivity and subsequent posttherapy cancer outcome. Further validation testing of RNR subunits as biomarkers for radiochemotherapy response is warranted.

  • Ribonucleotide reductase
  • Radiosensitivity
  • Cervical cancer

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Footnotes

  • This work was supported in part by NIH grant P30CA43703 for use of the Human Tissue Procurement and Pathology Core Facilities, Case Western Reserve University and the CASE Comprehensive Cancer Center (Cleveland, OH).

  • The authors declare no conflicts of interest.

  • This manuscript has been seen, read, and agreed upon in its content by all designated authors. It has not been submitted or published elsewhere.

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