THE IMPORTANCE OF METHYLTHIO-IMP FOR METHYLMERCAPTOPURINE RIBONUCLEOSIDE (ME-MPR) CYTOTOXICITY IN MOLT-F4 HUMAN-MALIGNANT T-LYMPHOBLASTS

被引：56

作者：

VOGT, MHJ ^{[1
]}

STET, EH ^{[1
]}

DEABREU, RA ^{[1
]}

BOKKERINK, JPM ^{[1
]}

LAMBOOY, LHJ ^{[1
]}

TRIJBELS, FJM ^{[1
]}

机构：

[1] CATHOLIC UNIV NIJMEGEN, ST RADBOUD HOSP, CTR PEDIAT ONCOL SE NETHERLANDS, DEPT PEDIAT, 6500 HB NIJMEGEN, NETHERLANDS

来源：

BIOCHIMICA ET BIOPHYSICA ACTA | 1993年 / 1181卷 / 02期

关键词：

METHYLMERCAPTOPURINE RIBONUCLEOSIDE; 6-MERCAPTOPURINE; 5-PHOSPHORIBOSYL-1-PYROPHOSPHATE; PURINE DENOVO SYNTHESIS; LYMPHOBLASTIC LEUKEMIA; CYTOTOXICITY;

D O I：

10.1016/0925-4439(93)90110-M

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The importance of methyl-thioIMP (Me-tIMP) formation for methylmercaptopurine ribonucleoside (Me-MPR) cytotoxicity was studied in Molt F4 cells. Cytotoxicity of Me-MPR is caused by Me-tIMP formation with concomitant inhibition of purine de novo synthesis. Inhibition of purine de novo synthesis resulted in decreased purine nucleotide levels and enhanced 5-phosphoribosyl-1-pyrophosphate (PRPP) levels, with concurrent increased pyrimidine nucleotide levels. The Me-tIMP concentration increased proportionally with the concentration of Me-MPR. High Me-tIMP concentration also caused inhibition of PRPP synthesis. Maximal accumulation of PRPP thus occurred at low Me-MPR concentrations. As little as 0.2 muM Me-MPR resulted already after 2 h in maximal inhibition of formation of adenine and guanine nucleotides, caused by inhibition of purine de novo synthesis by Me-tIMP. Under these circumstances increased intracellular PRPP concentrations could be demonstrated, resulting in increased levels of pyrimidine nucleotides. So, in Molt F4 cells, formation of Me-tIMP from Me-MPR results in cytotoxicity by inhibition of purine de novo synthesis.

引用

页码：189 / 194

页数：6

共 37 条

[1]

BENNETT LL, 1971, CANCER RES, V31, P152

[2] REVERSAL OF GROWTH INHIBITORY EFFECTS OF 6-METHYLTHIOPURINE RIBONUCLEOSIDE [J].