Abstract | PURPOSE: 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.
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Authors | Eric J Sorscher, Jeong S Hong, Paula W Allan, William R Waud, William B Parker |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 70
Issue 2
Pg. 321-9
(Aug 2012)
ISSN: 1432-0843 [Electronic] Germany |
PMID | 22760227
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antimetabolites, Antineoplastic
- Prodrugs
- Vidarabine Phosphate
- fludarabine phosphate
- Purine-Nucleoside Phosphorylase
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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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