Effect of very low doses of chemotherapeutic drugs on proangiogenic factors in tumor cells.

Abstract

e23013 Background: The efficacy of the metronomic use of conventional chemotherapeutic drugs in the clinic has been linked to their anti-angiogenic activity. However, the dose level for the metronomic use of the drugs with regard to anti-angiogenic activity is not known. In the current study, we aimed to study the effects of very low doses of 5-florouracil (5-FU), irinotecan and oxaliplatin on the synthesis of pro-angiogenic factors in tumor cells. Methods: We first determined the IC50 doses of 5-FU, irinotecan, and oxaliplatin in human tumor cell lines (HT-29: colon cancer cells, MCF-7: breast cancer cells and LNCaP: prostatic carcinoma cells). Then we applied the drugs to the assigned cells at the dose levels of IC50, -1log, -2log and -3log of IC50. The effects of the drugs on both gene expression and protein secretion levels of pro-angiogenic genes including vascular endothelial growth factor A (VEGF-A), basic-fibroblast growth factor (bFGF), matrix metalloproteinase-9 (MMP-9), platelet-derived growth factor-beta (PDGF-B), interleukin-8 (IL-8) and factor secretion by real-time PCR and sandwich ELISA. Results: The IC50 levels of 5-FU, irinotecan, and oxaliplatin in tumor cells were found as shown in the Table. We found that -1logIC50 dose level of 5-FU efficiently suppressed the pro-angiogenic genes both at the gene expression and protein secretion levels. However, the -2logIC50 and -3logIC50 dose levels of both irinotecan and oxaliplatin significantly inhibited gene expression and protein secretion. Conclusions: In conclusion, our results suggest that irinotecan and oxaliplatin could be used as anti-angiogenic agents at the very low doses. The -1logIC50 dose for 5-FU and the -2log and -3logIC50 doses of irinotecan and oxaliplatin could be further tested in animal models and clinical trials. Table. The IC50 dose levels of the drugs in tumor cell lines. [Table: see text]