Wong B K, DeFeo-Jones D, Jones R E, Garsky V M, Feng D M, Oliff A, Chiba M, Ellis J D, Lin J H
Drug Metabolism, Merck Research Laboratories, WP75A-203, West Point, PA 19486, USA.
Drug Metab Dispos. 2001 Mar;29(3):313-8.
Tumor-selective delivery of doxorubicin by a prostate-specific antigen (PSA)-targeted peptide conjugate prodrug of doxorubicin was demonstrated in a nude mouse xenograft model of human prostate cancer. The prodrug (referred to as doxorubicin conjugate) contains doxorubicin linked to a seven-amino acid peptide conjugate that was designed to increase delivery of doxorubicin to tumor sites through the hydrolytic properties of PSA, which prostate tumors express in high amounts. Following i.p. administration of the doxorubicin conjugate to mice, tumor exposure to doxorubicin was increased 2.5-fold as compared with that achieved after an equimolar dose of doxorubicin itself. However, in heart tissue, the site of clinical dose-limiting toxicity, doxorubicin concentrations observed after administration of doxorubicin conjugate were substantially lower than those in mice that received doxorubicin itself. While the prodrug provided selective delivery of doxorubicin to tumor tissue, there was substantial non-PSA-specific formation of doxorubicin in laboratory animals, a factor that would limit the extent of therapeutic gain of the prodrug. Following i.v. administration to mice, rats, dogs, and monkeys, about one-third of the dose was metabolized to doxorubicin. In tumor-bearing mice, the fraction of the dose metabolized to doxorubicin appeared even higher. This is likely the result of conjugate conversion to doxorubicin by both PSA-specific (in tumor) and non-PSA-specific proteolytic activities. In vitro studies provided further support for the PSA specificity of metabolism; LNCaP cells mediated rapid metabolism of the conjugate, while DuPRO-1 cells, which are deficient in PSA, were incapable of metabolism.
在人前列腺癌裸鼠异种移植模型中，证实了通过阿霉素的前列腺特异性抗原（PSA）靶向肽缀合物前药实现阿霉素的肿瘤选择性递送。该前药（称为阿霉素缀合物）包含与七氨基酸肽缀合物连接的阿霉素，该肽缀合物设计用于通过前列腺肿瘤中大量表达的PSA的水解特性，增加阿霉素向肿瘤部位的递送。向小鼠腹腔注射阿霉素缀合物后，与等摩尔剂量的阿霉素本身相比，肿瘤对阿霉素的暴露增加了2.5倍。然而，在临床剂量限制毒性的心脏组织中，给予阿霉素缀合物后观察到的阿霉素浓度明显低于接受阿霉素本身的小鼠。虽然前药提供了阿霉素向肿瘤组织的选择性递送，但在实验动物中存在大量非PSA特异性的阿霉素形成，这一因素将限制前药的治疗获益程度。向小鼠、大鼠、狗和猴子静脉注射后，约三分之一的剂量代谢为阿霉素。在荷瘤小鼠中，代谢为阿霉素的剂量分数似乎更高。这可能是由于PSA特异性（在肿瘤中）和非PSA特异性蛋白水解活性将缀合物转化为阿霉素的结果。体外研究为代谢的PSA特异性提供了进一步支持；LNCaP细胞介导缀合物的快速代谢，而缺乏PSA的DuPRO-1细胞则无法进行代谢。
