Studies on the mechanism of antitumor action of 2-desamino-2-methyl-5,8-dideazaisofolic acid.
Biochem Pharmacol
; 41(5): 781-7, 1991 Mar 01.
Article
en En
| MEDLINE
| ID: mdl-1998533
ABSTRACT
The new folate analogue, 2-desamino-2-methyl-5,8-dideazaisofolic acid, 2c, was synthesized and evaluated using a variety of biochemical and antitumor assays. For purposes of comparison, its 2-desamino, 2b, and 2-amino, 2a, counterparts, as well as N10-propargly-5,8-dideazafolic acid, 1a, and the corresponding 2-desamino, 1b, and 2-desamino-2-methyl, 1c, modifications were included in these studies. Compound 2c was found to be a potent inhibitor of the growth of L1210 and MCF-7 cells in culture, being only 2-fold and 5-fold less effective than 1c, respectively. However, although analogue 2c was 189-fold less inhibitory toward L1210 thymidylate synthase (TS) than 1c, its cytotoxicity was reversed completely by thymidine alone which suggests that the compound behaves as a TS inhibitor in cells. Enzymatically synthesized polyglutamates of 2c were substantially more inhibitory toward human TS than the parent compound. Compound 2c was the most efficient substrate for mammalian folyl-polyglutamate synthetase of the compounds studied having a Vmax/Km nearly 12-fold larger than 1c. Both 1c and 2c were effective inhibitors of the uptake of [3H]methotrexate into MOLT-4 cells, implying that each is efficiently transported into tumor cells. These results suggest that a weak inhibitor of TS in vitro can be a potent cytotoxic agent if it can readily gain entry into target cells and be converted to polyglutamated metabolites.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinazolinas
/
Timidilato Sintasa
/
Receptores de Superficie Celular
/
Antineoplásicos
Límite:
Animals
Idioma:
En
Revista:
Biochem Pharmacol
Año:
1991
Tipo del documento:
Article