Potentiation of the antitumor activity of alpha, alpha, alpha-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo.
Trifluorothymidine (FTD) is a thymidine analog that exhibits an antitumor activity through its inhibition of thymidylate synthase and its incorporation into DNA. However, FTD is rapidly hydrolyzed to an inactive form by thymidine phosphorylase (TP). We attempted to augment the antitumor activity of FTD by combining it with a potent and reversible inhibitor of TP, 5-chloro-6-(2-imino-propyrrolidin-1-yl) methyl-2, 4 (1H, 3H)-pyrimidinedione hydrochloride (TPI) in human tumor xenografts with a low sensitivity to 5-fluorouracil. The optimum ratio of TPI to FTD was determined by measuring the maximum plasma level of FTD after oral administration and the antitumor effect of FTD on human tumor xenografts in mice. When > 0.5 M of TPI and 1 M of FTD (10 mg/kg) were co-administered, the plasma FTD levels in mice and monkeys were elevated, almost reaching a maximal and constant value of 20-30 microg/ml and 15 microg/ml, respectively. When human gastrointestinal cancer cell lines (DLD-1, CO-3 and AZ521) were xenografted into nude mice, the antitumor activity of FTD was augmented by the co-administration of TPI, compared to that of FTD alone, and the ED50 value, used to indicate the antitumor effect, reached a maximum value (about 25, 20, and 10 mg/kg in the DLD-1, CO-3, and AZ521 tumors, respectively) when > 0.5 M of TPI was combined with 1 M of FTD. The oral administration of TPI markedly improved the FTD-induced toxicity, as evaluated by the decrease in the body weight of the mice. These results suggested that the optimum ratio of FTD to TPI was 1:0.5 M, enabling a high antitumor activity and a low toxicity. We further evaluated whether TPI inhibits TP-induced angiogenesis in a gelatin-sponge mouse model, based on the finding that TP is identical to platelet-derived endothelial cell growth factor. Ten and 30 mg/kg administration of TPI significantly inhibited TP-induced neovascularization in a dose-dependent manner in a mouse model. The above results suggest that the combination of TPI and an antitumor nucleoside, FTD, not only enhances the antitumor efficacy and decreases the toxicity of FTD, but also suppresses TP-induced angiogenesis.
Emura
Tomohiro
T
Cancer Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno-city, Saitama 357-8527, Japan. t-emura@taiho.co.jp
Suzuki
Norihiko
N
Fujioka
Akio
A
Ohshimo
Hideyuki
H
Fukushima
Masakazu
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013936:Thymidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014271:Trifluridine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
C506441:5-chloro-6-(2-imino-propyrrolidin-1-yl) methyl-2,4 (1H, 3H)-pyrimidinedione hydrochloride; D004791:Enzyme Inhibitors; D013939:Thymidine Phosphorylase; D014271:Trifluridine; D013936:Thymidine