Arnason Terra, Harkness Troy
Department of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada.
Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada.
Cancers (Basel). 2015 Oct 16;7(4):2063-82. doi: 10.3390/cancers7040877.
Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes of compounds. Our recent work suggests the anticoagulant protein Tissue Factor Pathway Inhibitor 1α (TFPI1α) plays a role in driving the development of multiple drug resistance (MDR); but not maintenance; of the MDR state. Other factors; such as the ABC transporter drug efflux pumps MDR-1/P-gp (ABCB1) and BCRP (ABCG2); are required for MDR maintenance; as well as development. The patient population struggling with therapeutic resistance specifically requires novel treatment options to resensitize these tumor cells to therapy. In this review we discuss the development, maintenance, and reversal of MDR as three distinct phases of cancer biology. Possible means to exploit these stages to reverse MDR will be explored. Early molecular detection of MDRcancers before clinical failure has the potential to offer new approaches to fightingMDRcancer.
许多癌症的早期检测和改进疗法正在提高生存率。尽管许多细胞毒性疗法已被批准用于治疗侵袭性或转移性癌症，但应答率较低，而且几乎普遍会出现获得性耐药。几十年来，癌症的化疗治疗一直包括使用阿霉素（DOX）等蒽环类药物，在侵袭性肿瘤中使用该药物似乎仍然是一种可行的选择，但与所有其他类别的化合物一样，对DOX也会产生耐药性。我们最近的研究表明，抗凝蛋白组织因子途径抑制剂1α（TFPI1α）在驱动多药耐药（MDR）的发展中起作用，但对MDR状态的维持不起作用。其他因素，如ABC转运蛋白药物外排泵MDR-1/P-糖蛋白（ABCB1）和乳腺癌耐药蛋白（BCRP，ABCG2），对MDR的维持以及发展都是必需的。特别是那些与治疗耐药作斗争的患者群体，特别需要新的治疗选择，以使这些肿瘤细胞对治疗重新敏感。在这篇综述中，我们将多药耐药的发展、维持和逆转作为癌症生物学的三个不同阶段进行讨论。我们将探索利用这些阶段来逆转多药耐药性的可能方法。在临床失败之前对多药耐药癌症进行早期分子检测，有可能为对抗多药耐药癌症提供新的方法。
