Delivery of high levels of anti-proliferative nucleoside triphosphates to CYP3A-expressing cells as a potential treatment for hepatocellular carcinoma.
OBJECTIVE
Hepatocellular carcinoma (HCC) is a life-threatening condition with only one drug treatment regimen approved for use. Oncolytic nucleosides are minimally effective against HCC putatively because of their inability to achieve cytotoxic levels of the active metabolite [nucleoside triphosphate (NTP)] in tumor cells at doses that are well tolerated. The aim of our studies was to explore the utility of CYP3A-activated prodrugs of cytarabine and fludarabine monophosphate for the treatment of HCC.


METHODS
Prodrugs of cytarabine and fludarabine monophosphates were evaluated for their ability to safely achieve NTP levels in the liver of normal mice that are cytotoxic to hepatoma cells.


RESULTS
While therapeutic levels of NTPs are achieved in the livers of normal rodents after administration of the prodrugs, only MB07133 achieved these levels without exhibiting signs of liver toxicity or myelosuppression.


CONCLUSIONS
As the levels of araCTP achieved in the liver at therapeutic doses are only toxic to proliferating cells (such as those in HCC tumors), but not the non-proliferative adjacent tissue, MB07133 treatment has the potential to be both efficacious and well tolerated in HCC patients.
MacKenna
Deidre A
DA
Departments of Biological Sciences and Medicinal Chemistry, Metabasis Therapeutics Inc, La Jolla, CA 92037, USA. dmackenna@ymail.com
Montag
Annika
A
Boyer
Serge H
SH
Linemeyer
David L
DL
Erion
Mark D
MD
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D016503:Drug Delivery Systems; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D009705:Nucleosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011355:Prodrugs; D013936:Thymidine / Q000378:metabolism; D014018:Tissue Distribution; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D009705:Nucleosides; D011355:Prodrugs; D003561:Cytarabine; D051544:Cytochrome P-450 CYP3A; D014740:Vidarabine; C024352:fludarabine; D013936:Thymidine