Anti-tumour effects of an antibody-carboxypeptidase G2 conjugate in combination with phenol mustard prodrugs.
Anti-tumour effects of an antibody-carboxypeptidase G2 conjugate in combination with phenol mustard prodrugs.
复制标题
抗体 - 羧肽酶G2结合物与苯酚芥末前药的抗肿瘤作用。
DOI：
10.1038/bjc.1995.469
复制
发表时间：
1995-11
影响因子：
8.8
通讯作者：
Melton, R G
中科院分区：
文献类型：
--
作者：
Blakey, D C;Davies, D H;Dowell, R I;East, S J;Burke, P J;Sharma, S K;Springer, C J;Mauger, A B;Melton, R G
ADEPT是一种用于治疗癌症的基于抗体的靶向策略。我们已经开发了两种新的前药，4-[N，N-双（2-氯乙基）氨基]-苯氧羰基-L-谷氨酸（PGP）和（S）-2-[N-[4-[N，N-双（2-氯乙基）氨基]-苯氧羰基]氨基]-4-（5-四唑基）丁酸（PTP），它们被细菌酶CPG 2切割以释放4-[N，N-双（2-氯乙基）氨基]苯酚药物。在体外，两种前药在LoVo结直肠肿瘤细胞中的效力比母体药物（1 h IC 50 = 1.4 μ M）低约100- 200倍。当与CPG 2和抗CEA单克隆抗体A5 B7的F（ab '）2片段的缀合物组合使用时，已经评价了这些前药在ADEPT中的效用。该缀合物显示特异性定位于在裸鼠中生长的已建立的LoVo肿瘤异种移植物，并且在72小时后达到最佳肿瘤-正常组织比率。在将A5 B7-CPG 2缀合物给予LoVo荷瘤小鼠后72小时，以引起6-8%体重减轻的剂量给予任一前药，导致肿瘤消退和生长延迟14-28天。PTP前药与高剂量的缀合物（10 mg kg-1）组合给出了最好的抗肿瘤活性，尽管是比PGP差10倍的CPG 2底物。单独的前药、单独的活性药物或前药与非特异性缀合物的组合在该肿瘤模型中具有最小的抗肿瘤活性。
ADEPT is an antibody-based targeting strategy for the treatment of cancer. We have developed two new prodrugs, 4-[N,N-bis(2-chloroethyl)amino]-phenoxycarbonyl-L- glutamic acid (PGP) and (S)-2-[N-[4-[N,N-bis(2-chloroethyl)amino]- phenoxycarbonyl]amino]-4-(5-tetrazoyl)butyric acid (PTP), which are cleaved by the bacterial enzyme CPG2 to release the 4-[N,N-bis(2-chloroethyl)amino] phenol drug. In vitro, both prodrugs are approximately 100- to 200-fold less potent than the parent drug (1 h IC50 = 1.4 microM) in LoVo colorectal tumour cells. These prodrugs have been evaluated for utility in ADEPT when used in combination with a conjugate of CPG2 and the F(ab')2 fragment of the anti-CEA monoclonal antibody, A5B7. The conjugate was shown to localise specifically to established LoVo tumour xenografts growing in nude mice and optimal tumour-normal tissue ratios were achieved after 72 h. Administration of either prodrug, at doses which cause 6-8% body weight loss, 72 h after administration of the A5B7-CPG2 conjugate to the LoVo tumour-bearing mice resulted in tumour regressions and growth delays of 14-28 days. The PTP prodrug in combination with a high dose of conjugate (10 mg kg-1) gave the best anti-tumour activity despite being a 10-fold worse substrate for CPG2 than PGP. Prodrug alone, active drug alone or prodrug in combination with a non-specific conjugate had minimal anti-tumour activity in this tumour model.