Comparison between CoFactor and Leucovorin activity applied in combination with 5-fluorouracil against two human colon cancer cell lines.
OBJECTIVE
The reduced folate leucovorin (LV) has been used for over 30 years as an enhancer of 5-fluorouracil (5-FU) antitumor activity. CoFactor (CoF) is a calcium salt of LV's active metabolite. Thus, administration of CoF can prevent decrease of intratumoral folate, which was recognized as the main reason for resistance of tumors to 5-FU treatment. The aim of this study was to investigate the cytotoxic activity and type of interactions for 5-FU and CoF applied in combination, in comparison to combination of 5-FU and LV, against human colon cancer cell lines LS- 174 and HT-29.


METHODS
The single agent activity was estimated in concentration range from 0.1 to 300 microM for 5-FU, CoF, and LV. In combined treatment each concentration of 5-FU (0.1, 1 and 10 microM) was matched with each concentration of CoF or LV (1, 10 and 100 microM). In both experiments the sulforodamine B cytotoxic test was used to assess drugs' activity after 72 h of incubation with cells. The type of interactions in combinations was calculated with the isobole method.


RESULTS
5-FU showed similar activity against LS-174 and HT-29 cell lines (IC50=30.8 and 21.6 microM, respectively). While LV affected both cell lines in a slightly proliferative manner, CoF showed cytotoxic effect on both cell lines, being more active against HT-29 cell (IC50=25.7 microM) and less active on LS-174 cells (IC50=72.6 microM). Addition of LV did not change the cytotoxicity of 5-FU, especially against LS-174 cells, and synergism was found only in HT-29 cells when LV was applied in high concentrations (10 and 100 microM). However, the combination of 5-FU with CoF revealed synergistic and additive interactions in LS-174 and HT-29 cells, respectively.


CONCLUSIONS
These results should be taken into consideration when planning or analyzing the results of clinical trials using combination of CoF and 5-FU.
Bjelogrlić
S K
SK
Department of Experimental Pharmacology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
Srdić
T
T
Radulović
S
S
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D002955:Leucovorin / Q000008:administration & dosage; D013763:Tetrahydrofolates / Q000008:administration & dosage; D014803:Vitamin B Complex / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D014803:Vitamin B Complex; D002955:Leucovorin; D005472:Fluorouracil