Acycloguanosyl 5'-thymidyltriphosphate, a thymidine analogue prodrug activated by telomerase, reduces pancreatic tumor growth in mice.
OBJECTIVE
Gemcitabine is the standard of care for metastatic and nonresectable pancreatic tumors. Phase II and III trials have not demonstrated efficacy of recently developed reagents, compared with gemcitabine alone; new chemotherapic agents are needed. Ninety percent of pancreatic tumors have telomerase activity, and expression correlates with tumor stage. We developed a thymidine analogue prodrug, acycloguanosyl 5'-thymidyltriphosphate (ACV-TP-T), that is metabolized by telomerase and releases the active form of acyclovir. We investigated the antitumor efficacy of ACV-TP-T in vitro and in vivo.


METHODS
We evaluated proliferation and apoptosis of human pancreatic cancer cells (PANC-1, MiaPaca2, BxPc3, PL45, and Su.86.86) incubated with ACV-TP-T. The presence of ACV-TP-T and its metabolite inside the cells were analyzed by mass spectrometry. In vivo efficacy was evaluated in nude mice carrying PANC-1 or MiaPaca2 pancreatic xenograft tumors.


RESULTS
The prodrug of ACV-TP-T was actively metabolized inside pancreatic cancer cells into the activated form of acyclovir; proliferation was reduced, apoptosis was increased, and the cell cycle was altered in pancreatic cancer incubated with ACV-TP-T, compared with controls. Administration of ACV-TP-T to mice reduced growth, increased apoptosis, and reduced proliferation and vascularization of pancreatic xenograft tumors.


CONCLUSIONS
ACV-TP-T, a thymidine analogue that is metabolized by telomerase and releases the active form of acyclovir, reduces proliferation and induces apoptosis of human pancreatic cancer cell lines in vitro and pancreatic xenograft tumors in mice.
FiorGen, Farmacogenomic Foundation, Sesto Fiorentino, Firenze, Italy.
Simone
S
Polvani
Massimo
M
Calamante
Valeria
V
Foresta
Elisabetta
E
Ceni
Alessandro
A
Mordini
Alessandro
A
Quattrone
Massimo
M
D'Amico
Claudio
C
Luchinat
Ivano
I
Bertini
Andrea
A
Galli
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006151:Guanosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D019098:Telomerase / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism*; D013942:Thymine Nucleotides / Q000032:analysis / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D011355:Prodrugs; D013942:Thymine Nucleotides; C556916:acycloguanosyl 5'-thymidyltriphosphate; D006151:Guanosine; D019098:Telomerase; D013936:Thymidine