Antitumor activity of 2-fluoro-2'-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase.
The selective expression of Escherichia coli purine nucleoside phosphorylase (PNP) in solid tumors has been successfully used to activate two purine nucleoside analogs [9-(2-deoxy-beta-D-ribofuranosyl)-6-methylpurine (MeP-dR) and 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-araA)] resulting in lasting tumor regressions and cures. E. coli PNP also cleaves 2-fluoro-2'-deoxyadenosine (F-dAdo) to 2-F-adenine, which is the toxic purine analog liberated from F-araA that has high bystander activity and is active against nonproliferating tumor cells. As F-dAdo is 3000 times better than F-araA as a substrate for E. coli PNP, we have evaluated its antitumor activity against D54 gliomas that express E. coli PNP and have characterized its in vivo metabolism in order to better understand its mechanism of action with respect to the other two agents. Like MeP-dR and F-araA-5'-monophosphate (F-araAMP, a prodrug of F-araA), treatment of mice bearing D54 tumors that express E. coli PNP with F-dAdo resulted in excellent antitumor activity. Although F-dAdo was as active as MeP-dR and better than F-araAMP, it was not dramatically better than either compound because of its short plasma half-life and the limited activation of F-adenine to toxic metabolites. Regardless, these results indicated that F-dAdo was also an excellent prodrug for use with gene vectors that deliver E. coli PNP to tumor cells.
Parker
William B
WB
Southern Research Institute, Birmingham, Alabama 35205, USA. parker@sri.org
Allan
Paula W
PW
Hassan
Abdalla E A
AE
Secrist
John A
JA
Sorscher
Eric J
EJ
Waud
William R
WR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003839:Deoxyadenosines / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D015964:Gene Expression Regulation, Bacterial; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D011355:Prodrugs; C030964:2'-fluoro-2'-deoxyadenosine; D011683:Purine-Nucleoside Phosphorylase