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靶向肿瘤毒素。

Targeting Toxins toward Tumors.

机构信息

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.

出版信息

Molecules. 2021 Feb 27;26(5):1292. doi: 10.3390/molecules26051292.

DOI:10.3390/molecules26051292
PMID:33673582
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7956858/
Abstract

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.

摘要

许多癌症疾病，例如前列腺癌和肺癌，发展非常缓慢。长春新碱、长春碱和紫杉醇等常用的化疗药物针对增殖状态的癌细胞。在发展缓慢的癌症疾病中，只有一小部分恶性细胞处于增殖状态，因此这些药物也会对快速增殖的良性组织造成伴随性损伤。许多毒素具有独立于良性或恶性细胞杀死所有状态细胞的能力。只有当这些毒素能够针对肿瘤进行选择性靶向时，才能将其用作化疗药物。此类毒素的例子有美登素、加利车霉素和沙普瑞林，它们都能以低微摩尔或纳摩尔浓度杀死细胞。使这些毒素靶向癌症组织的先进前药概念包括抗体导向酶前药疗法 (ADEPT)、基因导向酶前药疗法 (GDEPT)、凝集素导向酶激活前药疗法 (LEAPT) 和抗体药物偶联疗法 (ADC)，本文将对这些方法进行讨论。该综述还包括蛋白酶靶向嵌合体 (PROTAC) 用于敲低肿瘤发展所必需的受体的最新实例。此外，还将提到依赖于具有独特底物特异性的肿瘤过表达酶进行毒素靶向的方法。

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