Rink S M, Yarema K J, Solomon M S, Paige L A, Tadayoni-Rebek B M, Essigmann J M, Croy R G
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15063-8. doi: 10.1073/pnas.93.26.15063.
It is a goal of cancer chemotherapy to achieve the selective killing of tumor cells while minimizing toxicity to normal tissues. We describe the design of selective toxins forming DNA adducts that attract the estrogen receptor (ER), a transcription factor that is overexpressed in many human breast and ovarian tumors. The compounds consist of 4-(3-aminopropyl)-N,N-(2-chloroethyl)-aniline linked to 2-(4'-hydroxyphenyl)-3-methyl-5-hydroxy-indole. The former moiety is a DNA damaging nitrogen mustard and the latter is a ligand for the ER. The connection between these groups was refined to permit DNA adducts formed by the mustard portion of the molecule to present the ligand domain so that it was able to interact efficiently with the ER. By using 16-mers containing specific DNA adducts, it was determined that monoadducts and putative intrastrand crosslinks were preferred targets for the ER over interstrand crosslinks. A series of structurally related 2-phenylindole mustards was prepared, some of which were selectively toxic to the ER-positive breast cancer cell line MCF-7, as compared with the ER(-) negative line MDA-MB231. The ability both to bind to DNA and to interact significantly with the ER were essential to achieve selective lethality toward ER(+) cells. Compounds forming DNA adducts without the ability to bind receptor showed similar toxicities in the two cell lines. Several models could explain the selective toxicity of the mustard-phenylindole compounds toward ER(+) cells. The favored model suggests that a mustard-DNA adduct is shielded by the ER from DNA repair enzymes and hence cells possessing an abundance of the ER selectively retain the adduct and are killed.
癌症化疗的一个目标是实现对肿瘤细胞的选择性杀伤，同时将对正常组织的毒性降至最低。我们描述了一种选择性毒素的设计，该毒素形成吸引雌激素受体（ER）的DNA加合物，雌激素受体是一种在许多人类乳腺癌和卵巢肿瘤中过度表达的转录因子。这些化合物由与2-(4'-羟基苯基)-3-甲基-5-羟基吲哚相连的4-(3-氨基丙基)-N,N-(2-氯乙基)-苯胺组成。前一部分是一种DNA损伤性氮芥，后一部分是ER的配体。对这些基团之间的连接进行了优化，以使由分子的氮芥部分形成的DNA加合物呈现配体结构域，从而使其能够与ER有效相互作用。通过使用含有特定DNA加合物的16聚体，确定单加合物和推定的链内交联是ER相对于链间交联更倾向的靶点。制备了一系列结构相关的2-苯基吲哚氮芥，其中一些与ER(-)阴性细胞系MDA-MB231相比，对ER阳性乳腺癌细胞系MCF-7具有选择性毒性。与DNA结合并与ER显著相互作用的能力对于实现对ER(+)细胞的选择性杀伤至关重要。形成DNA加合物但无结合受体能力的化合物在两种细胞系中表现出相似的毒性。有几种模型可以解释氮芥-苯基吲哚化合物对ER(+)细胞的选择性毒性。最受青睐的模型表明，氮芥-DNA加合物被ER屏蔽，免受DNA修复酶的作用，因此拥有大量ER的细胞选择性地保留加合物并被杀死。
