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Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-Fluorouracil Antitumor Activity In Vitro and In Vivo
- Source :
- Oncology Research
- Publication Year :
- 2017
- Publisher :
- Computers, Materials and Continua (Tech Science Press), 2017.
-
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.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Time Factors
5-fluorouracil
colon cancer, sodium levofolinate, calcium levofolinate
Leucovorin
Apoptosis
Pharmacology
Mice
Reduced Folate Carrier Protein
0302 clinical medicine
Gene expression
Tumor Cells, Cultured
Chemistry
Drug Synergism
Calcium levofolinate (CaLV)
General Medicine
Dose–response relationship
colon cancer
Oncology
Fluorouracil
030220 oncology & carcinogenesis
SLC19A1
Thymidylate synthetase (TYMS)
medicine.drug
chemistry.chemical_element
Antineoplastic Agents
Calcium
Article
sodium levofolinate
03 medical and health sciences
Disodium levofolinate (NaLV)
calcium levofolinate
In vivo
Cell Line, Tumor
5-Fluorouracil (5-FU)
medicine
Animals
Humans
Cell Proliferation
Dose-Response Relationship, Drug
Synergism
Thymidylate Synthase
Xenograft Model Antitumor Assays
In vitro
Disease Models, Animal
030104 developmental biology
Cell culture
Subjects
Details
- ISSN :
- 09650407
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....ca8fc59b1f23d8f8db038eb124f7cc2e
- Full Text :
- https://doi.org/10.3727/096504017x14841698396900