دانلود مقاله لوسمی میلوئید حاد
چکیده
مقدمه
درمان های هدفمند
نظر متخصص
نتیجه گیری
منابع
Abstract
Introduction
Targeted therapeutics
Expert opinion
Conclusions
References
چکیده
مقدمه
با وجود پیشرفت در درمان لوسمی میلوئید حاد (AML)، بقای طولانی مدت کم است. در سال 1994، پیشنهاد شد که سلولهای بنیادی لوسمیک (LSCs) نقش کلیدی در بیماری‌های عودکننده و مقاوم دارند. LSCها از طریق چندین مکانیسم منحصر به فرد قادر به خود تجدید، تکثیر، تمایز، فرار ایمنی و مقاومت دارویی هستند. ابتکارات جدیدتر توسعه داروی لوسمی شامل تلاش هایی برای هدف قرار دادن LSC ها بوده است. با LSCها، چالش با چنین طراحی دارویی، یافتن راهی برای هدف قرار دادن انتخابی LSCها و در عین حال حفظ سلولهای بنیادی خونساز طبیعی (HSCs) است.
مناطق تحت پوشش
در این بررسی، ما دانش در حال تکامل زیست‌شناسی و فیزیولوژی منحصر به فرد LSC را در ادبیات علمی بررسی می‌کنیم، در حالی که به عوامل متعددی اشاره می‌کنیم که در طول سال‌ها برای هدف قرار دادن این زیر گروه از سلولهای لوسمی طراحی شده‌اند. بررسی ما شامل بحث در مورد سلولهای T گیرنده آنتی ژن کایمریک، آنتی‌بادی‌های مونوکلونال، کونژوگه‌های آنتی‌بادی-دارو علیه نشانگرهای سطح سلولی، اهداف مسیر سیگنالینگ، عوامل پرواپوپتوز، تنظیم‌کننده‌های اپی ژنتیک و موارد دیگر است.
نظر متخصص
همانطور که درک ما از پاتوفیزیولوژی پیچیده LSC ها همچنان در حال رشد است، واضح است که هدف قرار دادن چنین سلول های ناهمگن با موفقیت به یک رویکرد متفکرانه و چندوجهی نیاز دارد.
توجه! این متن ترجمه ماشینی بوده و توسط مترجمین ای ترجمه، ترجمه نشده است.
Abstract
Introduction
Despite advances in the treatment of acute myeloid leukemia (AML), long-term survival remains low. In 1994, it was proposed that leukemic stem cells (LSCs) played a key role in relapsed and refractory disease. LSCs are capable of self-renewal, proliferation, differentiation, immune evasion, and drug resistance through several unique mechanisms. More recent leukemia drug development initiatives have included efforts to target LSCs. With LSCs, the challenge with such drug design is finding a way to selectively target LSCs while sparing normal hematopoietic stem cells (HSCs).
Areas covered
In this review, we explore the evolving knowledge of the unique LSC biology and physiology in the scientific literature, while noting the several agents that have been designed throughout the years to target this subgroup of leukemic cells. Our review includes discussion on chimeric antigen receptor T cells, monoclonal antibodies, antibody-drug conjugates against cell surface markers, signaling pathway targets, pro-apoptotic agents, epigenetic regulators, and more.
Expert opinion
As our understanding of the intricate pathophysiology of LSCs continues to grow, it is clear that targeting such heterogenous cells successfully will require a thoughtful and multi-modal approach.
Introduction
Historically, the treatment of AML has consisted of induction chemotherapy with an anthracycline and cytarabine. Despite the advent of targeted therapies, relapse and progression of AML continue to be a challenge. Specifically, the five-year survival remains lower than desired at 29.5% [1]. Traditionally, AML relapse has been associated with residual disease following induction therapy [2–6]. Our knowledge regarding this subgroup of resistant residual cells continues to evolve. In 1994, Dick et al. characterized these cells as leukemic stem cells (LSCs) [7]. Dick and colleagues would later demonstrate that AML is organized in a hierarchical fashion, being driven by LSCs, similar to the normal hierarchy of hematopoiesis described by Metcalf in the 1960s [8,9]. Furthermore, LSCs were found to masquerade with a similar immunophenotype (CD34+ CD38-) as that of normal adult hematopoietic stem cells (HSCs), but with the potential of propagating malignant cells [10]. LSCs possess the ability for self-renewal, proliferation, differentiation, and drug evasion (Figure 1) [11]. At time of relapse, there is a 10-to-100-fold increase in LSCs [12]. As such, LSCs can give rise to recurrent AML and thus cure should ideally entail treatment capable of eradication of LSCs while sparing HSCs [13]. The extent to which LSCs influence leukemogenesis continues to be a controversial and highly studied topic.
Conclusions
The reconstitution of AML by transplanting CD34+ CD38- cells into immune-deficient mice over 28 years ago confirmed the existence of leukemia stem cells at a frequency of approximately one in 250,000 cells [117]. Since then, ample research culminated into a deeper understanding of the LSC cell architecture, biology, intracellular signaling pathways, and immunomodulatory functions that allow for its survival and pathogenesis in AML. Molecular analysis of the AML LSC population has specifically shown that survival requires several signaling functions via NF-κB, STAT, PI3 kinase pathways, self-renewal by means of regulatory pathways such as Wnt-β-catenin, Hedgehog and Notch, and evasion of apoptosis (Figure 2) [118].