Broggini M, Erba E, Ponti M, Ballinari D, Geroni C, Spreafico F, D'Incalci M
Laboratory of Cancer Chemotherapy, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Cancer Res. 1991 Jan 1;51(1):199-204.
N-Deformyl-N-(4-N-N,N-bis(2-chloroethylamino)benzoyl)distamy cin A (FCE 24517) is a novel cytotoxic and antitumor agent shortly to be investigated in phase I clinical trials. It was equally effective in inhibiting the growth of the murine L1210 line and of a subline (L1210/PAM) resistant to nitrogen mustards, whereas distamycin A was virtually inactive. The cellular uptake and retention of FCE 24517 and distamycin A were similar, thus excluding the possibility that this marked variation in cytotoxic activity was due to different intracellular concentrations of the two compounds. FCE 24517 did not appear to act as an inhibitor of macromolecule synthesis. As shown by radioactively labeled precursor incorporation only 24 h after drug treatment a significant inhibition of DNA synthesis was observed in L1210 or in L1210/PAM, when a marked proportion of cells was arrested in premitotic phase. FCE 24517 did not cause DNA breaks, DNA interstrand cross-links, or DNA-protein cross-links in L1210 cells exposed to active drug concentrations. A very low amount of radioactivity was found to be bound irreversibly to DNA in L1210 cells exposed for 1 h to [14C]FCE 24517. Using plasmid pBr322 DNA fragments in a modified version of the Maxam and Gilbert DNA sequencing technique we found no detectable binding of FCE 24517 to N-7-guanine (the major site of alkylation for classical alkylating agents), whereas some alkylations to adenine (presumably to N-3-adenine) were demonstrated. Thus it appears that FCE 24517 is a novel antitumor agent with a mode of action different from that of the drugs currently used in the clinic. In summary it is suggested that FCE 24517 acts by causing a few selective alkylations to adenines in the minor groove of DNA, although the precise base sequence necessary has yet to be elucidated.
N-去甲酰基-N-(4-N-N,N-双(2-氯乙基氨基)苯甲酰基)地司他丁A（FCE 24517）是一种新型细胞毒性和抗肿瘤药物，即将进入I期临床试验。它在抑制小鼠L1210细胞系以及对氮芥耐药的亚系（L1210/PAM）生长方面同样有效，而地司他丁A实际上没有活性。FCE 24517和地司他丁A的细胞摄取和滞留情况相似，因此排除了细胞毒性活性的显著差异是由于两种化合物细胞内浓度不同的可能性。FCE 24517似乎不是大分子合成的抑制剂。如药物处理仅24小时后放射性标记前体掺入所示，当相当比例的细胞停滞在有丝分裂前期时，在L1210或L1210/PAM细胞中观察到DNA合成受到显著抑制。FCE 24517在暴露于活性药物浓度的L1210细胞中不会导致DNA断裂、DNA链间交联或DNA-蛋白质交联。在暴露于[14C]FCE 24517 1小时的L1210细胞中，发现极少量放射性不可逆地与DNA结合。使用改良版Maxam和Gilbert DNA测序技术中的质粒pBr322 DNA片段，我们发现FCE 24517与N-7-鸟嘌呤（经典烷化剂的主要烷基化位点）没有可检测到的结合，而显示出对腺嘌呤（可能是N-3-腺嘌呤）的一些烷基化。因此，FCE 24517似乎是一种新型抗肿瘤药物，其作用方式与目前临床上使用的药物不同。总之，有人提出FCE 24517的作用是通过在DNA小沟中对腺嘌呤进行一些选择性烷基化，尽管所需的确切碱基序列尚未阐明。
