Efficacy and safety of FdUMP[10] in treatment of HT-29 human colon cancer xenografts.
Thymidylate synthase (TS) is the molecular target of fluoropyrimidine (FP) chemotherapy, and novel anticancer drugs effective against TS-overexpressing tumors are required to treat patients with FP-refractory solid tumors. We have evaluated the inhibition of cell proliferation in vitro and antitumor activity in vivo of FdUMP[10], an oligodeoxynucleotide 10mer in which 5-fluorouracil (5-FU) is the only nucleobase. FdUMP[10] is a pro-drug of FdUMP, the TS inhibitory metabolite of FPs. FdUMP[10] was 338-fold more potent than 5-FU at inhibiting cell proliferation in the NCI 60 cell line screen. The antitumor activity of FdUMP[10] was compared to 5-FU using H-T29 xenografts in female CD-1 athymic (nu+/nu+) mice. Treatment with FdUMP[10] as a single agent (40 mg/kg/daily x 5, i.v.) delayed tumor growth and resulted in a smaller mean tumor size (T/C value = 51%, p<0.001 compared with the control group). Treatment with 5-FU (25 mg/kg/daily x 5, i.p.) had similar results as single agent FdUMP[10] (T/C value = 65%, p=0.238 compared with the FdUMP[10] treated group. Simultaneous treatment of tumor-bearing mice with both drugs (FdUMP[10] plus 5-FU) further delayed tumor growth (T/C value = 36%; p=0.003 relative to 5-FU). The results from the combined treatment group were not, however, statistically significant relative to the group receiving single agent FdUMP[10] treatment (p=0.059). Histological examination revealed systemic damage was limited to the colonic epithelium in all treatment groups and was least extensive with single agent FdUMP[10] compared to the other treatment groups. The data support the concept that FdUMP[10] is a useful prototype of a novel type of FP that is likely to be more efficacious than FPs in clinical use.
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Changnian
C
Liu
Mark
M
Willingham
Jinqian
J
Liu
William H
WH
Gmeiner
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology; D012449:Safety; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D004791:Enzyme Inhibitors; C435305:FdUMP(10); D011355:Prodrugs; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase