Hussein A, Mioglou-Kalouptsi E, Papageorgiou A, Karapidaki I, Iakovidou-Kritsi Z, Lialiaris T, Xrysogelou E, Camoutsis C, Mourelatos D
Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Patras, Patras.
In Vivo. 2007 Mar-Apr;21(2):389-95.
Nitrosourea is decomposed under physiological conditions to react with biological macromolecules by two mechanisms: alkylation (with proteins and nucleic acids) and carbamoylation (with proteins but not nucleic acids). It has been suggested that the alkylating action is responsible for the therapeutic effects of nitrosoureas, and that the carbamoylation activity leads to toxicity effects. In order to reduce systemic toxicity and improve specificity and distribution for cancer therapy, 2-haloethyl nitrosourea has been esterified with modified steroids, which are used as biological platforms for transporting the alkylating agent to the tumor site in a specific manner. The cytogenetic and antineoplastic effect were studied of seven newly synthesized esters of N,N-bis(2-chloroethyl)alanyl carboxyl derivatives with a modified steroidal nucleus (compounds 1-7). As a very sensitive indicator of genotoxicity the Sister Chromatid Exchange (SCE) assay was used and as a valuable marker of cytostatic activity the cell Proliferation Rate Index (PRI) in cultures of normal human lymphocytes was used. The order of magnitude of the cytogenetic activity on a molar basis (15, 30, 120 microM) of the compounds was 7>>6>3>5>2>4>1. The most active compound 7 has an enlarged (seven carbon atoms) A ring modified with a lactam group (-NHCO-) with the nitrosourea moiety esterified at position 17 In the group of seven substances a correlation was observed between the magnitude of SCE response and the depression in PRI (r=-O, 65, p<0.001). According to the criterion of activity of National Cancer Institute (NCI), the order of antineoplastic activity of compounds on lymphoid L1210 leukemia is 7>6>2>5>4>3>1 and on lympocytic P388 leukemia cells is 7>2>6>5>4>3>1. The present results are in agreement with previous suggestions that the effectiveness in cytogenetic activity may well be correlated with antitumor effects [T/C: 248% for the compound 7 in 250 mg/kg b.w.; T/C: mean survival time of drug-treated animals (T) (excluding long term survivals) vs. corn-oil-treated controls (C)].
亚硝基脲在生理条件下会分解，并通过两种机制与生物大分子发生反应：烷基化（与蛋白质和核酸反应）和氨甲酰化（与蛋白质反应，但不与核酸反应）。有人提出，烷基化作用是亚硝基脲发挥治疗作用的原因，而氨甲酰化活性则导致毒性作用。为了降低全身毒性并提高癌症治疗的特异性和药物分布，2-卤代乙基亚硝基脲已与修饰的甾体进行酯化反应，这些甾体被用作生物平台，以特定方式将烷基化剂转运至肿瘤部位。研究了七种新合成的N,N-双（2-氯乙基）丙氨酰羧基衍生物与修饰甾体核的酯（化合物1-7）的细胞遗传学和抗肿瘤作用。作为遗传毒性的一个非常敏感的指标，采用了姐妹染色单体交换（SCE）试验，作为细胞抑制活性的一个有价值的标志物，采用了正常人淋巴细胞培养物中的细胞增殖率指数（PRI）。在摩尔浓度（15、30、120微摩尔）下，化合物的细胞遗传学活性的大小顺序为7>>6>3>5>2>4>1。活性最高的化合物7具有一个扩大的（七个碳原子）A环，该环被内酰胺基团（-NHCO-）修饰，亚硝基脲部分在17位酯化。在这七种物质中，观察到SCE反应的大小与PRI的降低之间存在相关性（r = -0.65，p < 0.001）。根据美国国立癌症研究所（NCI）的活性标准，化合物对淋巴样L1210白血病的抗肿瘤活性顺序为7>6>2>5>4>3>1，对淋巴细胞P388白血病细胞的活性顺序为7>2>6>5>4>3>1。目前的结果与先前的观点一致，即细胞遗传学活性的有效性可能与抗肿瘤作用密切相关[T/C：化合物7在250毫克/千克体重时为248%；T/C：药物治疗动物的平均存活时间（T）（不包括长期存活）与玉米油治疗对照组（C）相比]。
