sodium-oxybate and Lung-Neoplasms

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