Springer C J, Bagshawe K D, Sharma S K, Searle F, Boden J A, Antoniw P, Burke P J, Rogers G T, Sherwood R F, Melton R G
Department of Medical Oncology, Charing Cross Hospital, London, U.K.
Eur J Cancer. 1991;27(11):1361-6. doi: 10.1016/0277-5379(91)90010-b.
Three novel prodrugs have been designed for use as anticancer agents. Each is a bifunctional alkylating agent which has been protected to form a relatively inactive prodrug. They are designed to be activated to their corresponding alkylating agents at a tumour site by prior administration of an antitumour antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in a two-phase system called antibody-directed enzyme prodrug therapy (ADEPT). The Km and Vmax values for three different antibody-CPG2 conjugates were determined in relation to each prodrug. The Km values ranged from 4.5-12 mumol/l and the Vmax from 0.5-1.6 mumol/U/min. Athymic Nu/Nu mice with palpable transplanted human choriocarcinoma xenografts, which are resistant to conventional chemotherapy, were treated with anti-human chorionic gonadotropin antibodies conjugated to CPG2. This was followed by each of the three novel prodrugs. Significant increase in survival was obtained in three of the regimens tested using only one course of treatment. This demonstrates the potential of a tumour-localised bacterial enzyme to activate protected alkylating agents in order to eradicate an established human xenograft.
已设计出三种新型前药用作抗癌剂。每种都是双功能烷基化剂，已被保护以形成相对无活性的前药。它们的设计目的是在一种称为抗体导向酶前药疗法（ADEPT）的两相系统中，通过预先施用与细菌酶羧肽酶G2（CPG2）偶联的抗肿瘤抗体，在肿瘤部位被激活为相应的烷基化剂。测定了三种不同抗体-CPG2偶联物相对于每种前药的Km和Vmax值。Km值范围为4.5 - 12μmol/l，Vmax为0.5 - 1.6μmol/U/分钟。对常规化疗耐药的、有可触及移植人绒毛膜癌异种移植物的无胸腺裸鼠，用与CPG2偶联的抗人绒毛膜促性腺激素抗体进行治疗。随后给予三种新型前药中的每一种。在仅使用一个疗程治疗的三种测试方案中，存活率显著提高。这证明了肿瘤定位的细菌酶激活受保护烷基化剂以根除已建立的人异种移植物的潜力。
