THE CYTOTOXICITY, DNA CROSS-LINKING ABILITY AND DNA-SEQUENCE SELECTIVITY OF THE ANILINE MUSTARDS MELPHALAN, CHLORAMBUCIL AND 4-[BIS(2-CHLOROETHYL)AMINO] BENZOIC-ACID
THE CYTOTOXICITY, DNA CROSS-LINKING ABILITY AND DNA-SEQUENCE SELECTIVITY OF THE ANILINE MUSTARDS MELPHALAN, CHLORAMBUCIL AND 4-[BIS(2-CHLOROETHYL)AMINO] BENZOIC-ACID
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DOI：
10.1016/0006-2952(92)90038-k
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发表时间：
1992-07-07
影响因子：
5.8
通讯作者：
HARTLEY, JA
中科院分区：
文献类型：
--
作者：
SUNTERS, A;SPRINGER, CJ;HARTLEY, JA
本文比较了三种苯胺衍生物美法仑（L-PAM）、苯丁酸氮芥（CHL）和4-[双（2-氯乙基）氨基]苯甲酸（BAM）的体外细胞毒性、DNA链间交联能力和DNA序列选择性。使用磺基罗丹明B和四唑染料还原试验评估了人结肠腺癌LS 174 T和白血病K562细胞系的细胞毒性。对两种细胞系的细胞毒作用顺序为L-PAM > CHL > BAM，K562的敏感性低于LS 174 T。这不同于CHL > L-PAM > BAM的顺序，该顺序将从简单的化学反应性或水解速率预测，这些参数先前已被用作芳族氮化合物的生物效力的指标。通过碱性洗脱测定的细胞中的DNA链间交联显示与IC 50值相关。活性的排序顺序进一步预测的能力，在分离的DNA中产生链间交联剂。鸟嘌呤N-7烷基化的程度。使用改良的DNA测序技术评估，反映了细胞毒性和交联能力，但在同等水平的烷基化作用下，DNA序列选择性没有显著差异。这些数据表明，简单的化学反应性或水解速率不是一个很好的指标的DNA反应性或细胞毒性的苯胺类化合物的数量，而DNA链间交联能力，无论是在细胞中直接测量或在分离的DNA，给出了一个很好的指示生物活性。
Three aniline derivatives melphalan (L-PAM), chlorambucil (CHL) and 4-[bis(2-chloroethyl)amino] benzoic acid (BAM) have been compared on the basis of their in vitro cytotoxicities, DNA interstrand crosslinking ability and DNA sequence selectivity. Cytotoxicity was assessed in the human colonic adenocarcinoma LS174T and leukaemic K562 cell lines using the sulphorhodamine B and tetrazolium dye reduction assays. The order of cytotoxicities was L-PAM > CHL > BAM in both cell lines with K562 being less sensitive than LS174T. This was different from the order CHL > L-PAM > BAM which would be predicted from simple chemical reactivity or rate of hydrolysis, parameters which have been used previously as indicators of biological potency for aromatic nitrogen mustards. DNA interstrand crosslinking in cells as determined by alkaline elution showed a correlation with IC50 values. The ranking order of activity was further predicted by the ability of the agents to produce interstrand crosslinks in isolated DNA. The extent of guanine N-7 alkylation. assessed using a modified DNA sequencing technique, mirrored cytotoxicity and crosslinking ability, but at equivalent levels of alkylation there was no significant difference in DNA sequence selectivity. These data demonstrates that simple chemical reactivity or hydrolysis rate is not a good indicator of DNA reactivity or cytotoxicity for a number of aniline mustards, whereas DNA interstrand crosslinking ability either measured directly in cells or in isolated DNA, gives a good indication of biological activity.