Inhibition of metastasis of tumor cells overexpressing thymidine phosphorylase by 2-deoxy-L-ribose.
Thymidine phosphorylase (TP) catalyzes the reversible conversion of thymidine to thymine, thereby generating 2-deoxy-D-ribose-1-phosphate, which upon dephosphorylation forms 2-deoxy-D-ribose (D-dRib), a degradation product of thymidine. We have previously shown that D-dRib promotes angiogenesis and chemotaxis of endothelial cells and also confers resistance to hypoxia-induced apoptosis in some cancer cell lines. 2-Deoxy-L-ribose (L-dRib), a stereoisomer of D-dRib, can inhibit D-dRib anti-apoptotic effects and suppressed the growth of KB cells overexpressing TP (KB/TP cells) transplanted into nude mice. In this study, we examined the ability of L-dRib to suppress metastasis of KB/TP cells using two different models of metastasis. The antimetastatic effect of L-dRib was first investigated in a liver-metastasis model in nude mice inoculated with KB/TP cells. Oral administration of L-dRib for 28 days at a dose of 20 mg/kg/day significantly reduced the number of metastatic nodules in the liver and suppressed angiogenesis and enhanced apoptosis in KB/TP metastatic nodules. Next, we compared the ability of L-dRib and tegafur alone or in combination to decrease the number of metastatic nodules in organs in the abdominal cavity in nude mice receiving s.c. of KB/TP cells into their backs. L-dRib (20 mg/kg/day) was significantly (P < 0.05) more efficient than tegafur (100 mg/kg/day) in decreasing the number of metastatic nodules in organs in the abdominal cavity. By in vitro invasion assay, L-dRib also reduced the number of invading KB/TP cells. L-dRib anti-invasive activity may be mediated by its ability to suppress the enhancing effect of TP and D-dRib on both mRNA and protein expression of vascular endothelial growth factor and interleukin-8 in cultured KB cells. These findings suggest that L-dRib may be useful in a clinical setting for the suppression of metastasis of tumor cells expressing TP.
Department of Molecular Oncology, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima Japan.
Yuichi
Y
Nakajima
Takenari
T
Gotanda
Hiroshi
H
Uchimiya
Tatsuhiko
T
Furukawa
Misako
M
Haraguchi
Ryuji
R
Ikeda
Tomoyuki
T
Sumizawa
Hiroki
H
Yoshida
Shin-Ichi
S
Akiyama
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003855:Deoxyribose / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D016209:Interleukin-8 / Q000235:genetics; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D005641:Tegafur / Q000627:therapeutic use; D013939:Thymidine Phosphorylase / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D005641:Tegafur; D003855:Deoxyribose; D013939:Thymidine Phosphorylase