INTERACTIONS OF A NEW ANTI-TUMOR AGENT,1,4-DIHYDROXY-5,8-BIS[[2-[(2-HYDROXYETHYL)AMINO]-ETHYL]AMINO]-9,10-ANTHRACENEDIONE, WITH NUCLEIC-ACIDS
INTERACTIONS OF A NEW ANTI-TUMOR AGENT,1,4-DIHYDROXY-5,8-BIS[[2-[(2-HYDROXYETHYL)AMINO]-ETHYL]AMINO]-9,10-ANTHRACENEDIONE, WITH NUCLEIC-ACIDS
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DOI：
10.1016/0006-2952(81)90083-6
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发表时间：
1981-01-01
影响因子：
5.8
通讯作者：
MELAMED, MR
中科院分区：
文献类型：
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作者：
KAPUSCINSKI, J;DARZYNKIEWICZ, Z;MELAMED, MR
1，4-二羟基-5，8-双[[2-[（2-羟乙基）氨基]乙基]氨基]-9，10-蒽二酮（DHAQ）是一种新的抗肿瘤药物（NSC 279836），在1-10 ng/ml的浓度下，在体外抑制[小鼠Friend白血病细胞]在G2期的细胞进展。在G2中阻断的细胞含有增加量的RNA。药物与核染色质中的DNA和RNA结合，优先与核仁结合，并与细胞质中的RNA原位结合。光谱证据表明，DHAQ通过嵌入与天然[小牛胸腺DNA和小麦胚芽RNA]和合成核酸相互作用，尽管静电相互作用也在结合中发挥作用。所有的A和B结构核酸插入DHAQ，虽然没有明确的碱基特异性;与仅含有A-T碱基对的聚合物的相互作用比与其他聚合物的相互作用稍弱，并且交替聚合物表现出比均聚物对更强的亲和力。用SV 40 DNA进行电泳染料滴定提供了DHAQ通过嵌入与DNA结合的额外证据。药物的内在缔合常数（Ki）为1.8 × 104。106 M-1，其结合位点大小（n）为5个核苷酸，解旋角（v φ）为106 M-1。为26.5 °。因为DHAQ沉淀单链聚合物，所以药物可能与单链核酸的阴离子外部静电相互作用，随后堆积。DHAQ的药理学作用可能与药物嵌入双链核酸中有关，这可能会损害DNA转录和RNA加工。
1,4-Dihydroxyl-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione (DHAQ), a new antitumor drug (NSC 279836), suppressed cell progression [of mouse Friend leukemia cells] at the G2 phase in vitro at concentrations of 1-10 ng/ml. Cells blocked in G2 contained increased amounts of RNA. The drug bound to DNA and RNA in the nuclear chromatin with a prefrence for the nucleolus and to RNA in the cytoplasm of cells in situ. Spectroscopic evidence indicated that DHAQ interacts by intercalation with natural [calf thymus DNA and wheat germ RNA] and synthetic nucleic acids, although electrostatic interactions also play a part in the binding. All A and B structure nucleic acids intercalated DHAQ, although there was no clear base specificity; interactions with polymers containing only A-T base pairs were somewhat weaker than with other polymers and alternating polymers exhibited stronger affinity than did homopolymer pairs. Electrophoretic dye titration with SV40 DNA provided additional proof that DHAQ binds to DNA by intercalation. The intrinsic association constant of the drug (Ki) was 1.8 .times. 106 M-1, its binding site size (n) was 5 nucleotides and the unwinding angle (.vphi.) was 26.5.degree.. Because DHAQ precipitated single-stranded polymers, it is possible that the drug interacted electrostatically with the anionic exterior of single-stranded nucleic acids with subsequent stacking. The pharamacological effect of DHAQ may be related to drug intercalation into double-stranded nucleic acids which may impair DNA transcription and RNA processing.