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In vivo antitumor activity of intratumoral fludarabine phosphate in refractory tumors expressing E. coli purine nucleoside phosphorylase.

AbstractPURPOSE:
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.
CONCLUSION:
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.
AuthorsEric J Sorscher, Jeong S Hong, Paula W Allan, William R Waud, William B Parker
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 70 Issue 2 Pg. 321-9 (Aug 2012) ISSN: 1432-0843 [Electronic] Germany
PMID22760227 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antimetabolites, Antineoplastic
  • Prodrugs
  • Vidarabine Phosphate
  • fludarabine phosphate
  • Purine-Nucleoside Phosphorylase
Topics
  • Adenoviridae (genetics)
  • Animals
  • Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics, therapeutic use)
  • Bystander Effect (drug effects, genetics, radiation effects)
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm (drug effects, genetics, radiation effects)
  • Escherichia coli (genetics)
  • Genetic Therapy
  • Genetic Vectors
  • Glioma (drug therapy, genetics, radiotherapy)
  • Humans
  • Injections, Intralesional
  • Mice
  • Mice, Nude
  • Prodrugs (administration & dosage, pharmacokinetics, therapeutic use)
  • Purine-Nucleoside Phosphorylase (genetics, metabolism)
  • Transfection
  • Transplantation, Heterologous
  • Vidarabine Phosphate (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use)

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