Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study

J Transl Med. 2012 Apr 27;10:79. doi: 10.1186/1479-5876-10-79.

Abstract

Background: The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer.

Methods: Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3-AP treatments. Six women with platinum-resistant ovarian cancer underwent four-day 3-AP (96 mg/m(2), day one to four) and cisplatin (25 mg/m(2), day two and three) infusions every 21 days until disease progression or adverse effects prohibited further therapy. Pre-therapy ovarian cancer tissues were analyzed by immunohistochemistry for RNR subunit expression as an indicator of cisplatin plus 3-AP treatment response.

Results: 3-AP preceding cisplatin exposure in platinum-resistant ovarian cancer cells was not as effective as sequencing cisplatin plus 3-AP together in cell survival assays. Platinum-mediated DNA damage (i.e., γH2AX foci) resolved quickly after cisplatin-alone or 3-AP preceding cisplatin exposure, but persisted after a cisplatin plus 3-AP sequence. On trial, 25 four-day overlapping 3-AP and cisplatin cycles were administered to six women (median 4.2 cycles per patient). 3-AP-related methemoglobinemia (range seven to 10%) occurred in two (33%) of six women, halting trial accrual.

Conclusions: When sequenced cisplatin plus 3-AP, RNR inhibition restored platinum-sensitivity in platinum-resistant ovarian cancers. 3-AP (96 mg/m(2)) infusions produced modest methemoglobinemia, the expected consequence of ribonucleotide reductase inhibitors disrupting collateral proteins containing iron.

Trial registry: ClinicalTrials.gov NCT00081276.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Damage
  • Deoxycytosine Nucleotides / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gynecology
  • Histones / metabolism
  • Humans
  • Immunoblotting
  • Medical Oncology
  • Middle Aged
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / pathology
  • Platinum / adverse effects
  • Platinum / pharmacology
  • Platinum / therapeutic use*
  • Pyridines / pharmacology
  • Ribonucleotide Reductases / antagonists & inhibitors*
  • Ribonucleotide Reductases / metabolism
  • Thiosemicarbazones / pharmacology
  • Treatment Outcome

Substances

  • Deoxycytosine Nucleotides
  • Enzyme Inhibitors
  • H2AX protein, human
  • Histones
  • Pyridines
  • Thiosemicarbazones
  • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
  • 2'-deoxycytidine 5'-triphosphate
  • Platinum
  • Ribonucleotide Reductases

Associated data

  • ClinicalTrials.gov/NCT00081276