title: Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00081276.
authors.affiliation: Department of Radiation Oncology, University Hospitals of Cleveland, Cleveland, OH 44106, USA. charles.kunos@UHhospitals.org
authors.forename: Charles
authors.initials: C
authors.lastname: Kunos
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: Fadi W
authors.initials: FW
authors.lastname: Abdul-Karim
authors.forename: James
authors.initials: J
authors.lastname: Fanning
authors.forename: Ovadia
authors.initials: O
authors.lastname: Abulafia
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Bonebrake
authors.forename: Lydia
authors.initials: L
authors.lastname: Usha
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006176:Gynecology; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008495:Medical Oncology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010984:Platinum / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013882:Thiosemicarbazones / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D003845:Deoxycytosine Nucleotides; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C024107:2'-deoxycytidine 5'-triphosphate; D010984:Platinum; D012264:Ribonucleotide Reductases