Kratz Felix, Mansour Ahmed, Soltau Jens, Warnecke Andre, Fichtner Iduna, Unger Clemens, Drevs Joachim
Tumor Biology Center, Freiburg, Germany.
Arch Pharm (Weinheim). 2005 Oct;338(10):462-72. doi: 10.1002/ardp.200500130.
Prostate-specific antigen (PSA) is a serine protease that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this work, we developed albumin-binding prodrugs with the structures MT-Ser-Ser-Tyr-Tyr- Ser-Gly-DOXO, MT-Asn-Ser-Ser-Tyr-Phe-Gln-DOXO (MT = maleimidotriethyleneglycol acid; DOXO = Doxorubicin) or EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO (EMC = epsilon-maleimidocaproic acid; X = amino acid). The maleimide Doxorubicin derivatives bound rapidly to the cysteine-34 position of endogenous and exogenous albumin and were efficiently cleaved by PSA at the P(1)-P'(1) scissile bond, releasing a respective Doxorubicin dipeptide (Ser-Gly-DOXO or Phe-Gln-DOXO). The derivative containing arginine residues (EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO) exhibited excellent water solubility for intravenous administration. Subsequent biological evaluation was focused on a PSA-negative xenograft model (PC 3) and a PSA-positive xenograft model (CWR22) in order to assess the selectivity of our therapeutic approach. EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO showed no in vivo activity in the PSA-negative PC 3 model, but good activity in the CWR22 PSA-positive model that was comparable to Doxorubicin.
前列腺特异性抗原（PSA）是一种丝氨酸蛋白酶，在前列腺癌中过表达，是从前药制剂中选择性释放抗癌剂的分子靶点。在这项工作中，我们开发了具有MT-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO、MT-Asn-Ser-Ser-Tyr-Phe-Gln-DOXO（MT = 马来酰亚胺三甘醇酸；DOXO = 多柔比星）或EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO（EMC = ε-马来酰亚胺己酸；X = 氨基酸）结构的白蛋白结合前药。马来酰亚胺多柔比星衍生物迅速与内源性和外源性白蛋白的半胱氨酸-34位点结合，并被PSA在P(1)-P'(1)可裂解键处有效切割，释放出相应的多柔比星二肽（Ser-Gly-DOXO或Phe-Gln-DOXO）。含有精氨酸残基的衍生物（EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO）表现出优异的水溶性，适合静脉给药。随后的生物学评估集中在PSA阴性异种移植模型（PC 3）和PSA阳性异种移植模型（CWR22）上，以评估我们治疗方法的选择性。EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO在PSA阴性的PC 3模型中没有体内活性，但在CWR22 PSA阳性模型中具有良好的活性，与多柔比星相当。
