INTERACTIONS OF ANTITUMOR AGENTS AMETANTRONE AND MITOXANTRONE (NOVATRONE) WITH DOUBLE-STRANDED DNA
INTERACTIONS OF ANTITUMOR AGENTS AMETANTRONE AND MITOXANTRONE (NOVATRONE) WITH DOUBLE-STRANDED DNA
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DOI：
10.1016/0006-2952(85)90275-8
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发表时间：
1985-12-15
影响因子：
5.8
通讯作者：
DARZYNKIEWICZ, Z
中科院分区：
文献类型：
--
作者：
KAPUSCINSKI, J;DARZYNKIEWICZ, Z
使用计算机辅助分光光度技术研究了米托蒽醌和阿美蒽醌与天然和合成核酸在水性介质[0.15 NaCl，5 mM 4-(2-羟乙基)-1-哌嗪-乙磺酸(Hepes)，pH 7.0，25°]中的相互作用。单体和二聚体形式的药物及其与低药物/磷酸盐比率 (D/P) 下的 DNA 复合物的吸收光谱已经建立。与游离配体单体的光谱相比，后者发生红移并且具有较低的振幅；这种变化与已经确立的药物-核酸相互作用的插入模式一致。药物-DNA 平衡已使用配体-聚合物非合作相互作用的 McGhee-von Hippel 模型进行了研究，并对药物二聚化进行了校正。尽管米托蒽醌的抗肿瘤药物效力比阿美蒽醌强两个数量级，但两种药物的内在关联常数 (Ki) 具有相似的大小。此外，没有观察到这两种药物的显着 DNA 碱基特异性（以 Ki 表示，各种同聚物的值）。因此，无论碱基组成如何，与 DNA 结合的插入模式与这些药物的药理活性之间没有明显的相关性。在较高的 D/P 比率下，通过光谱学和光散射测量检测到第二种结合模式。均聚物对和仅包含 dC 和 dC 的聚合物特别容易受到这种第二种类型的结合的影响。考虑到这种次要类型的结合可能是药物抗肿瘤特性的原因。
Interactions of Mitoxantrone and Ametantrone with natural and synthetic nucleic acids in aqueous medium [0.15 NaCl, 5 mM 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (Hepes), pH 7.0, 25.degree.] have been studied using computer-aided spectrophotometric techniques. Absorption spectra of the drugs in monomeric and dimeric form and their complexes with DNAs at low drug/phosphate ratios (D/P) have been established. The latter were red-shifted and had lower amplitude as compared with the spectra of the free ligand''s monomer; the change is consistent with the already well-established intercalative mode of drug-nucleic acid interaction. Drug-DNA equilibria have been studied using the McGhee-von Hippel model of noncooperative ligand-polymer interaction, with the correction for dimerization of drugs. Although Mitoxantrone is two orders of magnitude more potent an antitumor drug than Ametantrone, the intrinsic association constants (Ki) of both drugs were of similar magnitude. Also, no significant DNA-base specificity for either of the drugs (measured as Ki, value for various homopolymers) was observed. Therefore, no correlation was apparent between the intercalative mode of binding to DNA, regardless of base composition, and the pharmacological activity of these drugs. At higher D/P ratios, a secondary mode of binding as detected by both spectroscopy and light-scattering measurement. Homopolymer-pairs and polymers containing only all and dC were especially susceptible to this secondary type of binding. The possibility that this secondary type of binding may be responsible for the antitumor properties of the drugs is considered.