title: In vivo antitumor activity of intratumoral fludarabine phosphate in refractory tumors expressing E. coli purine nucleoside phosphorylase.
abstract: OBJECTIVE
  Systemically administered fludarabine phosphate (F-araAMP) slows growth of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (PNP). However, this treatment has been limited by the amount of F-araAMP that can be administered in vivo. The current study was designed to (1) determine whether efficacy of this overall strategy could be improved by intratumoral administration of F-araAMP, (2) test enhancement of the approach with external beam radiation, and (3) optimize recombinant adenovirus as a means to augment PNP delivery and bystander killing in vivo.
  
  
  METHODS
  The effects of systemic or intratumoral F-araAMP in mice were investigated with human tumor xenografts (300 mg), in which 10 % of the cells expressed E. coli PNP from a lentiviral promoter. Tumors injected with an adenoviral vector expressing E. coli PNP (Ad/PNP; 2 × 10(11) viral particles, 2 times per day × 3 days) and the impact of radiotherapy on tumors treated by this approach were also studied. Radiolabeled F-araAMP was used to monitor prodrug activation in vivo.
  
  
  RESULTS
  Intratumoral administration of F-araAMP in human tumor xenografts expressing E. coli PNP resulted in complete regressions and/or prolonged tumor inhibition. External beam radiation significantly augmented this effect. Injection of large human tumor xenografts (human glioma, nonsmall cell lung cancer, or malignant prostate tumors) with Ad/PNP followed by intratumoral F-araAMP resulted in excellent antitumor activity superior to that observed following systemic administration of prodrug.
  
  
  CONCLUSIONS
  Activation of F-araAMP by E. coli PNP results in destruction of large tumor xenografts in vivo, augments radiotherapy, and promotes robust bystander killing. Our results indicate that intratumoral injection of F-araAMP leads to ablation of tumors in vivo with minimal toxicity.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sorscher@uab.edu
authors: Eric J
authors: EJ
authors: Sorscher
authors: Jeong S
authors: JS
authors: Hong
authors: Paula W
authors: PW
authors: Allan
authors: William R
authors: WR
authors: Waud
authors: William B
authors: WB
authors: Parker
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024201:Bystander Effect / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004926:Escherichia coli / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D011683:Purine-Nucleoside Phosphorylase