title: Protracted dosing of the lipophilic camptothecin analogue AR-67 in non-small cell lung cancer xenografts and humans.
abstract: OBJECTIVE
  Although preclinical studies on camptothecin antitumor effect have demonstrated the superiority of low-dose protracted dosing, these findings were not replicated in the clinic. 7-t-butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a camptothecin analogue currently under investigation in early phase clinical trials. To maximize the therapeutic potential of AR-67, we sought to identify factors that affect response to treatment.
  
  
  METHODS
  After determining the maximum tolerated dose using neutropenia as a toxicity endpoint, xenografts received AR-67 under varying dosing schedules and were monitored for survival. On the last treatment day, tumor tissue was collected and topoisomerase 1 (Top1), γH2AX, caspase 3 and PARP protein content was evaluated. AR-67 plasma and tumor pharmacokinetics were also studied in mice and cancer patients who were administered AR-67 as a 1-h intravenous infusion on days 1, 4, 8, 12 and 15 every 21 days.
  
  
  RESULTS
  Low-dose protracted dosing schedules increased animal survival compared to less frequent, but higher-dose courses and the expression of Top1 and γH2AX were schedule dependent. Fatigue and neutropenia were the dose-limiting toxicities identified in patients receiving AR-67. Finally, elimination of AR-67 from the tumor site was slower in both xenografts and tumor of a patient enrolled in the pilot clinical trial.
  
  
  CONCLUSIONS
  We demonstrated that low-dose protracted dosing schedules of AR-67 are therapeutically effective and Top1 reflects the biological activity of AR-67 in xenografts. Moreover, the tumor pharmacokinetics as well as the efficacy and safety of AR-67 given intermittently to cancer patients warrant further investigation.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Room 323, Lexington, KY, 40536, USA.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsakalozou
authors.forename: Eyob D
authors.initials: ED
authors.lastname: Adane
authors.forename: Yali
authors.initials: Y
authors.lastname: Liang
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Arnold
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
mesh_terms: D000328:Adult; D000818:Animals; D062005:Biopsy, Large-Core Needle; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017646:Organosilicon Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D010865:Pilot Projects; D011897:Random Allocation; D016019:Survival Analysis; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D017646:Organosilicon Compounds; D059004:Topoisomerase I Inhibitors; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D002166:Camptothecin