title: A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells.
abstract: BACKGROUND
  We tested the hypothesis that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) may enhance response to re-treatment with gemcitabine by enhancing intracellular uptake of gemcitabine in a phase II study.
  
  
  METHODS
  Patients who had prior exposure to gemcitabine as a first-line treatment of advanced non-small-cell lung cancer (NSCLC) were given weekly infusions of 3-AP and gemcitabine for 3 weeks followed by 1 week of rest, repeated every 28 days. Plasma and peripheral blood mononuclear cells (PBMCs) were collected to evaluate the effect of 3-AP on pharmacokinetics and intracellular uptake of gemcitabine.
  
  
  RESULTS
  Twelve patients were treated with a median of two treatment cycles without objective response, hence the study was terminated at interim analysis. Four patients had stable disease and the median time to progression was 3 months (95% confidence interval, CI: 1.7 to 9.1 months). Grade 3 toxicities included neutropenia (two patients), hypoxia (three patients) and dyspnea (one patient). Four patients developed reversible symptomatic methemoglobinemia during 3-AP infusion, with mild to moderately elevated methemoglobin levels that ranged from 7.8 to 17.6% of the total hemoglobin concentration. Limited pharmacokinetic data did not suggest any clinically relevant pharmacological influence of 3-AP on gemcitabine.
  
  
  CONCLUSIONS
  3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves.
authors.affiliation: Department of Clinical Oncology, Sir Y.K. Pao Center for Cancer, Hong Kong Cancer Institute, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Ngan Shing Street, Shatin, New Territories, Hong Kong. brigette@clo.cuhk.edu.hk
authors.forename: Brigette
authors.initials: B
authors.lastname: Ma
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Eng Huat
authors.initials: EH
authors.lastname: Tan
authors.forename: Kwok Chi
authors.initials: KC
authors.lastname: Lam
authors.forename: Ross
authors.initials: R
authors.lastname: Soo
authors.forename: Swan Swan
authors.initials: SS
authors.lastname: Leong
authors.forename: Ling Zhi
authors.initials: LZ
authors.lastname: Wang
authors.forename: Frankie
authors.initials: F
authors.lastname: Mo
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Benny
authors.initials: B
authors.lastname: Zee
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage; D013882:Thiosemicarbazones / Q000008:administration & dosage; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011725:Pyridines; D013882:Thiosemicarbazones; D003841:Deoxycytidine; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D000093542:Gemcitabine