The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy
The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy
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DOI：
10.1021/jm0101996
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发表时间：
2001-11-22
影响因子：
7.3
通讯作者：
Freidinger, RM
中科院分区：
文献类型：
--
作者：
Garsky, VM;Lumma, PK;Freidinger, RM
阿霉素（Dox）可以在一定程度上稳定前列腺癌；然而，由于全身毒性，主要是心脏毒性和免疫抑制，其使用受到限制。阿霉素前药的施用，旨在允许肿瘤选择性激活，将减少对活性药物的全身暴露，从而提高治疗指数。前列腺特异性抗原（PSA）是一种丝氨酸蛋白酶，具有凝乳胰蛋白酶样活性，是激肽激酶基因家族的成员。据推测，PSA的生理作用是使精液液化，因为它有能力裂解精液蛋白-精凝胶I和II。血清PSA水平已被发现与恶性前列腺细胞的数量密切相关。使用前列腺中被PSA酶切割的前药，原则上应该在肿瘤部位产生高浓度的局部细胞毒剂，同时限制全身暴露于活性药物。构建了PSA处理后的卵磷脂裂解图谱。对主要裂解位点两侧的氨基酸残基进行系统修饰，合成了一系列短肽，这些短肽可被PSA高效水解。随后将选定的多肽偶联到阿霉素上，得到了一系列阿霉素肽偶联物，这些偶联物在体外和体内被评价为分泌psa的肿瘤细胞的靶向前药。从这些研究中，我们选择了glutaryl - hy - ala - ser - chg - gln - ser - leu -dox， 27作为多肽-阿霉素结合物，具有最佳的物理和生物学特性。相对于不分泌psa的DuPRO细胞系，化合物27对人前列腺分泌psa的LNCaP细胞具有20倍以上的选择性。在裸鼠异种移植螺柱中，27在低于MTD的剂量下使PSA水平降低95%，肿瘤重量降低87%。阿霉素和Leu-Dox（13）在最大耐受剂量下对降低循环PSA和肿瘤负荷无效。在这些结果的基础上，我们选择了27个进行进一步的研究，以评估其抑制人类前列腺癌细胞生长和肿瘤发生的能力。
Doxorubicin (Dox) can provide some stabilization in prostate cancer; however, its use is limited because of systemic toxicities, primarily cardiotoxicity and immunosuppression. The administration of a prodrug of doxorubicin, designed to permit selective activation by the tumor, would reduce general systemic exposure to the active drug and would thereby increase the therapeutic index. Prostate specific antigen (PSA) is a serine protease with chymotrypsin-like activity that is a member of the kallikrein gene family. PSA's putative physiological role is the liquefaction of semen by virtue of its ability to cleave the seminal fluid proteins semenogelins I and II. Serum PSA levels have been found to correlate well with the number of malignant prostate cells. The use of a prodrug which is cleaved by the enzyme PSA in the prostate should in principle produce high localized concentrations of the cytotoxic agent at the tumor site while limiting systemic exposure to the active drug. Cleavage maps following PSA treatment of human semenogelin were constructed. Systematic modification of the amino acid residues flanking the primary cleavage site led to the synthesis of a series of short peptides which were efficiently hydrolyzed by PSA. Subsequent coupling of selected peptides to doxorubicin provided a series of doxorubicin-peptide conjugates which were evaluated in vitro and in vivo as targeted prodrugs for PSA-secreting tumor cells. From these studies we selected Glutaryl-Hyp-Ala-Ser-Chg-Gln-Ser-Leu-Dox, 27, as the peptide-doxorubicin conjugate with the best profile of physical and biological properties. Compound 27 has a greater than 20-fold selectivity against human prostate PSA-secreting LNCaP cells relative to the non-PSA-secreting DuPRO cell line. In nude mouse xenograft stud: es, 27 reduced PSA levels by 95% and tumor weight by 87% at a dose below its MTD. Both doxorubicin and Leu-Dox (13) were ineffective in reducing circulating PSA and tumor burden at their maximum tolerated doses. On the basis of these results, we selected 27 for further Study to assess its ability to inhibit human prostate cancer cell growth and tumorigenesis.