Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Molecules. 2018 Nov 8;23(11):2915. doi: 10.3390/molecules23112915.
Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential.
除了抗凝作用外，肝素衍生物和硫酸乙酰肝素（HS）类似物（功能定义的 HS 类似物）在肿瘤学中的治疗潜力与其结合和调节 HS 结合蛋白功能的能力有关，这些 HS 结合蛋白在癌症生长和进展中具有关键作用。结构/功能决定因素的定义和化学修饰的引入使肝素衍生物能够具有大大降低或缺失的抗凝活性，但保留/增强的抗癌活性。这些研究为揭示 HS 类似物对肝素酶、选择素和生长因子受体信号的抑制作用的结构要求以及限制副作用铺平了道路。实际上，HS 类似物通过基于它们对肿瘤细胞和肿瘤微环境各种成分的影响的多靶点作用机制来影响肿瘤的生物学行为。有证据表明，免疫调节可以参与这些药物的抗肿瘤活性。在几种肿瘤模型中，这些药物与标准治疗联合使用时显著增强了抗肿瘤效果。虽然第一批 HS 类似物正在进行早期临床评估，但需要更好地了解在某些恶性肿瘤或亚组中有利于抗肿瘤作用的分子环境，以充分发挥其潜力。
