Abstract:
:The formation, retention and biological activity of the polyglutamate metabolites of the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) has been investigated in L1210 murine leukaemia cells grown in vitro. CB3717 polyglutamates were measured by HPLC using high specific activity 3H-CB3717. Following the exposure of cells to 50 microM CB3717 for 6, 12 and 24 hr total cellular radioactivity corresponded to 4.5 +/- 1.5, 6.8 +/- 3.6 and 5.9 +/- 3.4 microM drug derived material, respectively. Of this material, greater than 70%, 57 +/- 3% and 51 +/- 5% was in the form of unchanged CB3717 at 6, 12 and 24 hr respectively. The remaining radioactivity was associated with polyglutamate metabolites of CB3717, predominantly the tetra and pentaglutamate forms. Following the removal of extracellular drug after incubation for 24 hr and resuspension in drug free medium, unchanged CB3717 was lost rapidly from the cells such that after 6 hr it accounted for only 5% of total cellular radioactivity. In contrast, levels of CB3717 tetra and pentaglutamates declined solely due to dilution during cell division. Measurement of the whole cell TS activity by 3H-deoxyuridine incorporation into DNA indicated that, despite the loss of unchanged CB3717 from the cell, enzyme activity remained suppressed (less than 10% of control) for at least 24 hr after resuspension in drug free medium. The TS inhibitory activity of the polyglutamated metabolites of CB3717 was investigated using enzyme purified from L1210 cells. As inhibitors, the metabolites were 26-, 87-, 119- and 114-fold more potent than CB3717 as the di-, tri-, tetra- and pentaglutamate forms, respectively. However, as inhibitors of dihydrofolate reductase prepared from rat liver, CB3717 polyglutamates were no more than 5-fold More potent than the parent compound. This study has shown that CB3717 can undergo polyglutamation in tumour cells and that the metabolites are preferentially retained giving rise to prolonged TS inhibition. By virtue of their potent TS inhibitory activity these metabolites are, therefore, most probably the intracellular effectors of CB3717 cytotoxicity.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Sikora E,Jackman AL,Newell DR,Calvert AHdoi
10.1016/0006-2952(88)90094-9subject
Has Abstractpub_date
1988-11-01 00:00:00pages
4047-54issue
21eissn
0006-2952issn
1873-2968pii
0006-2952(88)90094-9journal_volume
37pub_type
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