Cytotoxicity and radiosensitising activity of synthesized dinitrophenyl derivatives of 5-fluorouracil
Journal Title: DARU Journal of Pharmaceutical Sciences - Year 2012, Vol 20, Issue 0
Abstract
Dual functional agents in which nitroaromatic or nitroheterocyclic compounds are attached through a linker unit to mustards and aziridines have shown higher cytotoxicities than the corresponding counterparts to both aerobic and hypoxic cells and enhanced radiosensitizing activity. In the present investigation cytotoxicity and radiosensitizing activity of 2,4-dinitrobenzyl, 2,4-dinitrobenzoyl, and 2,4-dinitrophenacetyl derivatives of 5-fluorouracil which was assumed to release cytotoxic active quinone methidide and 5-fluorouracil under hypoxic conditions on HT-29 cell line under both aerobic and hypoxic conditions was investigated.Methods 5-fluorouracil derivative X-XIII were prepared by the reaction of the corresponding di-nitro substituted benzyl, benzoyl and phenacetyl halides with 5-fluorouracil protected at N-1 with di-t-butoxydicarbonate (BOC) in dimethyl formamide (DMF) in the presence of the potassium carbonate followed by hydrolysis of the blocking group by potassium carbonate in methanol. Cytotoxicity of fluorouracil VIII and tested compounds X-XIII against HT-29 cell line under both aerobic and hypoxic conditions after 48 hrs incubation were measured by determination of the percent of the survival cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and percent of the dead cells using propidium iodide(PI)-digitonine assay and results were used to calculate the corresponding IC50 values. Radiosensitization experiments were carried out by irradiation of the incubations with a 60Co source and clonogenic assay was performed to determine the cell viabilities following treatment with the tested compounds and/or radiation. Sensitization Enhancement Ratio (SER) of each tested compound was obtained from the radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results and major conclusion Findings of the present study showed that alkylation or acylation of 5-fluorouracil result in compounds which have little or no cytotoxicity and radiosensitizing activity under aerobic conditions, but have high cytotoxicity and radiosensitizing effects under hypoxic conditions. Furthermore radiosensitizing activities of compounds under hypoxic conditions increased by increase in their concentrations and SER of the tested 5-FU derivatives at concentrations higher than 50 μmol were equal or higher than 1.6 which is the minimum effective SER of a radiosensitizer in an in vitro assay.
Authors and Affiliations
Khosrou Abdi, Ali Khalaj, Syeed-Naser Ostad, Mohammad Reza Khoshayand
Keywords
Related Articles
- EP ID EP135281
- DOI -
- Views 84
- Downloads 0
In vitro and in vivo activities of ticarcillin-loaded nanoliposomes with different surface charges against pseudomonas aeruginosa (ATCC 29248)
Pseudomonas aeruginosa exhibits multiple antibiotic resistance mechanisms. Different studies have shown that entrapment of antibiotics into liposomes could increase their anti- Pseudomonas activity. The objectives of thi...
Natural gums as sustained release carriers: development of gastroretentive drug delivery system of ziprasidone HCl
Objective of this study is to show the potential use of natural gums in the development of drug delivery systems. Therefore in this work gastro retentive tablet formulations of ziprasidone HCl were developed using simple...
Cost-effectiveness of adding-on new antiepileptic drugs to conventional regimens in controlling intractable seizures in children
Background and purpose of the study Intractable seizures are a subgroup of epileptic disorders challenging the physicians' skills to become controlled. Showing resistance towards common pharmacotherapy, they demand newer...
Cost effectiveness of Iran national plasma contract fractionation program
Plasma derived medicines (PDM) including immunoglobulins, clotting factors and albumin are life saving medicines which due to their high costs are inaccessible for many patients living in developing countries. By contrar...
Umbelliprenin is cytotoxic against QU-DB large cell lung cancer cell line but anti-proliferative against A549 adenocarcinoma cells
Umbelliprenin is a natural compound, belonging to the class of sesquiterpene coumarins. Recently, umbelliprenin has attracted the researchers' attention for its antitumor activities against skin tumors. Its effect on lun...