INCREASED TOXICITY OF 9‐β‐D‐ARABINOFURANOSYLADENINE IN THE PRESENCE OF AN INHIBITOR OF ADENOSINE DEAMINASE *
INCREASED TOXICITY OF 9‐β‐D‐ARABINOFURANOSYLADENINE IN THE PRESENCE OF AN INHIBITOR OF ADENOSINE DEAMINASE *
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在腺苷脱氨酶抑制剂存在下，9-β-D-阿拉伯呋喃糖腺嘌呤的毒性增加*
DOI：
10.1111/j.1749-6632.1977.tb21939.x
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发表时间：
1977
影响因子：
5.2
通讯作者：
Seymour S. Cohen
中科院分区：
文献类型：
--
作者：
W. Plunkett;Seymour S. Cohen
腺嘌呤核苷类似物9-p-~-阿拉伯呋喃糖基腺嘌呤（ara-A）是一种有效的人类抗病毒剂（综述见参考文献I）。人体研究和临床试验表明，ara-A和一些衍生物也具有有希望的抗癌活性。本实验室的研究表明，小鼠成纤维细胞（L细胞）与ara-A和5 ′-磷酸盐一起孵育导致DNA合成的抑制6和随后细胞活力的丧失。本文报道了阿糖胞苷A（ara-A）对荷瘤小鼠DNA合成的抑制作用，并延长了荷瘤小鼠的生存时间。H ~*'酶的研究表明，这种作用可能是由于9-β-~-阿拉伯呋喃腺嘌呤（ara-ATP）12 - 14抑制DNA聚合酶，而9-β-阿拉伯呋喃腺嘌呤（ara-ADP）和ara-ADP抑制核糖核苷酸还原酶所致。ATP.12 - 15在与100 pM ara-A孵育4小时期间，ara-ATP在L细胞中积累到20 pM，该水平比哺乳动物DNA聚合酶的ara-ATP Ki高20倍。“此外，ara-ATP作为DNA聚合酶的底物，并被掺入DNA中的核苷酸间连接。其中一些现象可以解释ara-A对染色体的破坏作用。然而，通过腺苷脱氨酶将ara-A脱氨为相对无毒的9-β-~-阿拉伯呋喃糖基次黄嘌呤（ara-Hx）限制了潜在的治疗效果ara-A.fi。当指数生长的L细胞与2 × 10 - 1 M ara-A孵育时，超过一半的细胞在24小时内被杀死，如通过从含ara-A的培养基6-H中洗涤后细胞形成集落的能力所确定的（图I）。4小时后对生长培养基的分析表明，48%的ara-A已脱氨为ara-Hx，到24小时，仅剩下ara-Hx。如图1所示，用2x M ara-Hx孵育的细胞的生长速率仅略低于对照细胞。因此，在与ara-A孵育24小时后恢复的细胞生长可能归因于ara-A的总脱氨基，伴随着细胞ara-ATP的周转和降低至低于抑制水平。
The adenine nucleoside analog 9-p-~-arabinofuranosyladenine (ara-A) is an effective antiviral agent in humans (reviewed in Reference I ) . Studies in humans and clinical trials have demonstrated that ara-A and some derivatives also possess promising anticancer activity in Studies in this laboratory had shown that incubation of mouse fibroblasts (L cells) with ara-A and the 5'-phosphate results in an inhibition of D N A synthesis6 and the subsequent loss of cell viability."" Injection of ara-A into tumor-bearing mice inhibits tumor cell D N A synthesisg and increases the survival time of the host.H-*' Enzymic studies suggested that these effects resulted from the inhibition of DNA polymerase by 9-fi-~-arabinofuranosyladenine 5'-triphosphate (ara-ATP)l2-l4 and possibly from inhibition of ribonucleotide reductase by 9-pD-arabinofuranosyladenine 5'-diphosphate (ara-ADP) and ara-ATP.l2-l5 During a 4-hr incubation with 100 pM ara-A, ara-ATP accumulated to 20 pM in L cells,'6 a level 20-fold greater than the Ki of ara-ATP for a mammalian DNA polymerase." I n addition, ara-ATP serves as a substrate for DNA polymerase and is incorporated into internucleotide linkage in DNA.'+'" Some of these phenomena may explain the damaging effect of ara-A on chromosomes.'" However, deamination of ara-A by adenosine deaminase to the relatively nontoxic 9-p-~-arabinofuranosylhypoxanthine (ara-Hx) limits the potential therapeutic effectiveness of ara-A.fi,Q When exponentially growing L cells were incubated with 2 x lo-' M ara-A, more than half of the cells were killed in 24 hr, as determined by the ability of the cells to form colonies after being washed from ara-A-containing medium6-H (FIGURE I ) . Analysis of the growth medium after 4 hr indicated that 48% of the ara-A had been deaminated to ara-Hx, and by 24 hr, only ara-Hx remained. As shown in FIGURE I , the growth rate of cells incubated with 2 x M ara-Hx is only slightly less than the control cells. Therefore, the renewed cell growth after 24 hr of incubation with ara-A may be attributed to the total deamination of ara-A accompanied by the turnover and decrease of cellular ara-ATP to less than inhibitory levels.