Charles Kunos, Tomas Radivoyevitch, Fadi W Abdul-Karim, James Fanning, Ovadia Abulafia, Albert J Bonebrake, Lydia Usha
Index: J. Transl. Med. 10 , 79, (2012)
Full Text: HTML
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.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.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.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.ClinicalTrials.gov NCT00081276.
Structure | Name/CAS No. | Molecular Formula | Articles |
---|---|---|---|
![]() |
Triapine
CAS:143621-35-6 |
C7H9N5S |
Trypanotoxic activity of thiosemicarbazone iron chelators.
2015-03-01 [Exp. Parasitol. 150 , 7-12, (2015)] |
Iron-targeting antitumor activity of gallium compounds and n...
2013-03-10 [Antioxid. Redox Signal. 18(8) , 956-72, (2013)] |
Vacuolar-ATPase Inhibition Blocks Iron Metabolism to Mediate...
2015-07-15 [Cancer Res. 75 , 2863-74, (2015)] |
Ribonucleotide reductase inhibition enhances chemoradiosensi...
2010-11-01 [Radiat. Res. 174(5) , 574-81, (2010)] |
Deoxynucleoside salvage facilitates DNA repair during ribonu...
2011-10-01 [Radiat. Res. 176(4) , 425-33, (2011)] |
Home | MSDS/SDS Database Search | Journals | Product Classification | Biologically Active Compounds | Selling Leads | About Us | Disclaimer
Copyright © 2024 ChemSrc All Rights Reserved