ROLE OF THYMIDYLATE SYNTHETASE-ACTIVITY IN DEVELOPMENT OF METHOTREXATE CYTOTOXICITY

被引:95
作者
MORAN, RG
MULKINS, M
HEIDELBERGER, C
机构
[1] UNIV SO CALIF,COMPREHENS CANC CTR,LOS ANGELES,CA 90033
[2] NEW YORK STATE DEPT HLTH,ROSWELL PK MEM INST,JAMES T GRACE JR CANC DRUG CTR,BUFFALO,NY 14263
关键词
D O I
10.1073/pnas.76.11.5924
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Methotrexate (MTX) inhibition of the growth of mouse or human leukemia cells in culture was partially prevented by either thymidine (dThd) or hypoxanthine. 5-Fluoro-2'-deoxyuridine (FdUrd) also decreased the growth-inhibitory potency of MTX in the presence of small concentrations of 5-formyltetrahydrofolate (citrovorum factor) and sufficient exogenous dThd to support the synthesis of thymidylate nucleotides by salvage mechanisms. In addition, citrovorum factor-induced reversal of MTX was several orders of magnitude more efficient in the presence of both FdUrd and dThd than in the presence of dThd alone or in the absence of both nucleosides. Likewise, the presence of FdUrd (3 μM) and dThd (5.6 μM) completely prevented the lethality of 0.3 mM MTX to L1210 cells in culture medium supplemented with micromolar concentrations of citrovorum factor. We propose that this protection against the cytotoxic effects of MTX by dThd, hypoxanthine, and FdUrd have a common biochemical mechanism - namely, inhibition of the de novo synthesis of thymidylate by either a direct [FdUrd; inhibition of thymidylate synthetase (thymidylate synthase; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45)] or indirect (dThd and hypoxanthine; feedback inhibition by anabolites on ribonucleotide reductase and deoxycytidylate deaminase) effect. The resultant decreased rate of loss of reduced folates due to de novo thymidylate synthesis would allow a higher degree of inhibition of dihydrofolate reductase to be endured without damage to the cell.
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页码:5924 / 5928
页数:5
相关论文
共 53 条
[1]  
BERTINO JR, 1964, J BIOL CHEM, V239, P479
[2]  
BERTINO JR, 1977, CANCER RES, V37, P327
[3]   NATURALLY OCCURRING FOLATES IN BLOOD AND LIVER OF RAT [J].
BIRD, OD ;
MCGLOHON, VM ;
VAITKUS, JW .
ANALYTICAL BIOCHEMISTRY, 1965, 12 (01) :18-&
[4]  
BORSA J, 1969, MOL PHARMACOL, V5, P318
[5]  
BORSA J, 1969, CANCER RES, V29, P737
[6]  
BORSA J, 1969, MOL PHARMACOL, V5, P303
[7]  
BOWEN D, 1978, CANCER RES, V38, P219
[8]  
DOLNICK BJ, 1977, J BIOL CHEM, V252, P7697
[9]   LIVER DISEASE ASSOCIATED WITH METHOTREXATE TREATMENT OF PSORIATIC PATIENTS [J].
DUBIN, HV ;
HARRELL, ER .
ARCHIVES OF DERMATOLOGY, 1970, 102 (05) :498-+
[10]  
ENSMINGER W, 1977, P AM ASSOC CANC RES, V18, P109