title: Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer.
abstract: OBJECTIVE
  The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer.
  
  
  RESULTS
  A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p < 0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining.
  
  
  METHODS
  The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model.
  
  
  CONCLUSIONS
  These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low-dose exposure correlates to alterations in cell cycle and increased p21 expression.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA USA.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Aljuffali
authors.forename: Jason N
authors.initials: JN
authors.lastname: Mock
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Costyn
authors.forename: Ha
authors.initials: H
authors.lastname: Nguyen
authors.forename: Tamas
authors.initials: T
authors.lastname: Nagy
authors.forename: Brian S
authors.initials: BS
authors.lastname: Cummings
authors.forename: Robert D
authors.initials: RD
authors.lastname: Arnold
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019772:Topotecan / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019772:Topotecan