@Article{096504017X14841698396900,
AUTHOR = {Antonello Di Paolo, Paola Orlandi, Teresa Di Desidero, Romano Danesi, Guido Bocci},
TITLE = {Simultaneous, But Not Consecutive, Combination With Folinate Salts  Potentiates 5-Fluorouracil Antitumor Activity In Vitro and In Vivo},
JOURNAL = {Oncology Research},
VOLUME = {25},
YEAR = {2017},
NUMBER = {7},
PAGES = {1129--1140},
URL = {http://www.techscience.com/or/v25n7/56895},
ISSN = {1555-3906},
ABSTRACT = {The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in 
the landscape of colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 
5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on 
human colon cancer cells exposed to 5-FU, calcium (CaLV), or disodium (NaLV) levofolinate or their simultaneous and sequential combination for 24 and 72 h. TYMS and SLC19A1 gene expression was performed 
with real-time PCR. In vivo experiments were performed in xenografted nude mice, which were treated with 
5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24-h treatment 
in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 
24 and 72 h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 
24 h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed 
the enhanced antitumor activity of the 5-FU + NaLV simultaneous combination with a good toxicity profile, 
whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations
potentiated the antiproliferative effects of the drugs.},
DOI = {10.3727/096504017X14841698396900}
}