Viktorsson Kristina, Lewensohn Rolf, Zhivotovsky Boris
Unit of Medical Radiobiology, Department of Oncology/Pathology, Cancer Center Karolinska, Karolinska Institute, S-171 76 Stockholm, Sweden.
Adv Cancer Res. 2005;94:143-96. doi: 10.1016/S0065-230X(05)94004-9.
Apoptosis and necrosis are two morphologically distinct forms of cell death that are important for maintaining of cellular homeostasis. Almost all agents can provoke either response when applied to cells; however, the duration of treatment and the dose of the used agents determine which type of death (apoptosis or necrosis) is initiated. The response of tumors to chemo-, radio-, and hormone therapy or to treatment with biologically active agents may depend at least in part on the propensity of these tumors to undergo cell death. Some tumors, e.g., leukemias, small cell lung cancer, and seminomas, respond quickly to first-line therapy; this fast response is thought to result from induction of apoptosis. Solid tumors, on the other hand, usually respond slowly and less effectively, with cell death characterized not only by apoptosis but also by necrosis, or mitotic catastrophe. It is likely that resistance of tumors to treatment might be associated with defects in, or dysregulation of, different steps of the apoptotic pathways. Several attempts were undertaken to use the knowledge of these defects to design new drugs, which might either activate or re-activate the apoptotic machinery of tumor cells. Here we discuss the apoptotic pathways and their role in therapy resistance of human malignancies. Although such studies are still in progress, they offer great promise for future cancer therapy. We hope that some of these agents will turn out to be valuable additions to the future therapeutic arsenal, which will most probably include a combination of conventional cytotoxic drugs and molecular target-based pro-apoptotic drugs.
凋亡和坏死是细胞死亡的两种形态学上不同的形式，对于维持细胞内稳态很重要。几乎所有的药物作用于细胞时都能引发这两种反应中的一种；然而，治疗的持续时间和所用药物的剂量决定了引发哪种类型的死亡（凋亡或坏死）。肿瘤对化疗、放疗、激素治疗或生物活性剂治疗的反应可能至少部分取决于这些肿瘤发生细胞死亡的倾向。一些肿瘤，如白血病、小细胞肺癌和精原细胞瘤，对一线治疗反应迅速；这种快速反应被认为是由凋亡诱导所致。另一方面，实体瘤通常反应缓慢且效果较差，其细胞死亡不仅以凋亡为特征，还以坏死或有丝分裂灾难为特征。肿瘤对治疗的耐药性可能与凋亡途径不同步骤的缺陷或失调有关。人们进行了几次尝试，利用对这些缺陷的了解来设计新药，这些新药可能会激活或重新激活肿瘤细胞的凋亡机制。在这里，我们讨论凋亡途径及其在人类恶性肿瘤治疗耐药性中的作用。尽管此类研究仍在进行中，但它们为未来的癌症治疗带来了巨大希望。我们希望其中一些药物将成为未来治疗武器库中有价值的补充，未来的治疗武器库很可能包括传统细胞毒性药物和基于分子靶点的促凋亡药物的联合使用。
