sodium-oxybate and Kidney-Neoplasms

We investigated the antitumor vasculogenesis and antitumor activity of gamma-hydroxybutyric acid (GHB), a metabolite of UFT. In a mouse dorsal air sac (DAS) assay, UFT demonstrated a wide spectrum of anti-tumor vasculogenesis except for AZ-521 tumor. Although the expression of vascular endothelial growth factor (VEGF) was detected in almost all tumor cell lines used in the DAS assays, expression of basic fibroblast growth factor (bFGF) was only detected in the AZ-521 tumor. GHB inhibited the chemotactic migration and morphological changes of human umbilical vein endothelial cells (HUVECs) induced by VEGF at IC50 values of 2.8 and 0.31 microM respectively. In addition to these in vitro assays, GHB blocked tumor growth of MC-5, a human breast cancer, in a xenograft model at inhibition rate of 37%. Moreover, GHB showed an additive effect in combination with 5-FU in this model. These results indicate that the anti-tumor vasculogenesis activity of GHB is involved in part in the antitumor effect of UFT.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Drug Combinations; Endothelial Growth Factors; Gastrointestinal Neoplasms; Humans; Kidney Neoplasms; Lymphokines; Mice; Mice, Nude; Neoplasm Transplantation; Sodium Oxybate; Tegafur; Tumor Cells, Cultured; Uracil; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

UFT, a drug composed of uracil and tegafur at the molar ratio of 4:1, is an orally active agent for the treatment of a wide variety of malignant tumours. Using a murine dorsal air sac (DAS) assay, we have previously shown that UFT and its metabolites, gamma-hydroxybutyric acid (GHB) and 5-fluorouracil (5-FU), inhibited the angiogenesis induced by murine renal cell carcinoma. Here we report that UFT was more effective than other fluorinated pyrimidines such as 5-FU and doxifluridine (5'-DFUR) in blocking the angiogenic responses elicited by five human cancer cell lines which produced high levels of vascular endothelial growth factor (VEGF), but no detectable fibroblast growth factor-2 (FGF-2) in vitro. In contrast, UFT was unable to block the angiogenic response to one human gastric cancer cell line which produced both VEGF and FGF-2 in vitro. However, the production or secretion of VEGF by these cells was unaffected by GHB and 5-FU treatment. Interestingly, GHB suppressed the chemotactic migration and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF, without inhibiting their DNA synthesis. Since GHB did not affect the FGF-2-driven activities in HUVECs, its action appears to be VEGF-selective. On the other hand, 5-FU inhibited DNA synthesis and migration of HUVECs stimulated by both VEGF and FGF-2, and tube formation driven by VEGF, suggesting that 5-FU is cytotoxic to endothelial cells. The inhibitory effects of 5-FU, and especially those GHB, were reproduced under in vivo condition using the DAS assay. The VEGF-mediated angiogenesis was significantly inhibited by UFT, 5-FU, and especially by GHB. We propose that the selective inhibitory effects of GHB on VEGF-mediated responses of endothelial cells are involved in the anti-angiogenic activity of UFT.

Topics: Angiogenesis Inhibitors; Animals; Antimetabolites, Antineoplastic; Breast Neoplasms; Carcinoma; Carcinoma, Renal Cell; Chemotaxis; Colonic Neoplasms; DNA Replication; Drug Combinations; Endothelial Growth Factors; Endothelium, Vascular; Female; Fibroblast Growth Factor 2; Floxuridine; Fluorouracil; Humans; Intercellular Signaling Peptides and Proteins; Kidney Neoplasms; Lung Neoplasms; Lymphokines; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Neoplasm Proteins; Neovascularization, Pathologic; Prodrugs; Prostheses and Implants; Recombinant Proteins; Sodium Oxybate; Stomach Neoplasms; Tegafur; Tumor Cells, Cultured; Uracil; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Xenograft Model Antitumor Assays

We investigated the effects of UFT and its metabolites, GHB and GBL, on angiogenesis induced by tumor cells in a dorsal air sac (DAS) assay in mice. Five tumor cell lines (murine renal carcinoma; RENCA, human gastric cancer; 4-1ST, human small-cell lung carcinoma; LX-1, and human colon carcinoma; DLD-1, KM-20C) were used in the DAS assay. In this model, UFT demonstrated a significant anti-angiogenic activity in a dose-dependent manner while 5-FU (19 mg/kg/day) and 5'-DFUR (200 mg/kg/day) were less effective. Moreover, tegafur (FT), a component of UFT, and gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL), in vivo metabolites of UFT, inhibited angiogenesis induced by RENCA cells. The inhibitory effects of 5-FU, GHB, and GBL on angiogenesis were increased with administration by continuous infusion, providing a suitable pharmacokinetic profile. These results suggest that GHB and GBL are involved in the expression of anti-angiogenic activity of UFT.

Topics: 4-Butyrolactone; Animals; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Sodium Oxybate; Stomach Neoplasms; Tegafur; Tumor Cells, Cultured; Uracil