Excellent in vivo bystander activity of fludarabine phosphate against human glioma xenografts that express the escherichia coli purine nucleoside phosphorylase gene.
Escherichia coli purine nucleoside phosphorylase (PNP) expressed in tumors converts relatively nontoxic prodrugs into membrane-permeant cytotoxic compounds with high bystander activity. In the present study, we examined tumor regressions resulting from treatment with E. coli PNP and fludarabine phosphate (F-araAMP), a clinically approved compound used in the treatment of hematologic malignancies. We tested bystander killing with an adenoviral construct expressing E. coli PNP and then more formally examined thresholds for the bystander effect, using both MuLv and lentiviral vectoring. Because of the importance of understanding the mechanism of bystander action and the limits to this anticancer strategy, we also evaluated in vivo variables related to the expression of E. coli PNP (level of E. coli PNP activity in tumors, ectopic expression in liver, percentage of tumor cells transduced in situ, and accumulation of active metabolites in tumors). Our results indicate that F-araAMP confers excellent in vivo dose-dependent inhibition of bystander tumor cells, including strong responses in subcutaneous human glioma xenografts when 95 to 97.5% of the tumor mass is composed of bystander cells. These findings define levels of E. coli PNP expression necessary for antitumor activity with F-araAMP and demonstrate new potential for a clinically approved compound in solid tumor therapy.
Hong
Jeong S
JS
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
Waud
William R
WR
Levasseur
Dana N
DN
Townes
Tim M
TM
Wen
Hui
H
McPherson
Sylvia A
SA
Moore
Bryan A
BA
Bebok
Zsuzsa
Z
Allan
Paula W
PW
Secrist
John A
JA
Parker
William B
WB
Sorscher
Eric J
EJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008979:Moloney murine leukemia virus / Q000235:genetics; D011683:Purine-Nucleoside Phosphorylase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D011683:Purine-Nucleoside Phosphorylase