مبانی نظری و پیشینه پژوهشی اثر 3 و 6 هفته تمرین هوازی بر فاکتورهای رشدی و التهابی کبدی متعاقب القای دوزهای مختلف دوکسوروبیسین

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فهرست محتوا

 

فصل دوم

2-1. مقدمه 14

2-2.  مبانی نظری پژوهش 14

2-2-1. آنتراسایکلینها و تاریخچه 14

2-2-2. دوکسوروبیسین به عنوان یک عامل درمانی 17

2-2-3. سمیت ناخواسته دوکسوروبیسین 20

2-2-4. سمیت ناخواسته دوکسوروبیسین در کبد 23

2-2-5 .آناتومی و فیزیولوژی بافت کبد 26

2-2-6.سرطان در کبد 28

2-2-7. مکانیزم التهاب در سرطان 29

2-2-8. ساختار و فیزیولوژی فاکتورهای التهابی 31

2-2-8-1.  اینتر لوکین 10 (IL-10) 31

2-2-8-2. اینترفرون گاما (IFNγ) 33

2-2-9. دستگاه رشدی 35

2-2-10. پروتئینهای متصل شونده به IGF 41

2-3. پیشینه پژوهش 43

2-3-1. مطالعات دوکسوروبیسین در حیطه غیر ورزشی و ورزشی 43

فهرست منابع

 

مقدمه

در این فصل سعی شده ابتدا مبانی نظری دوکسوروبیسین و اثرات سمی آن بر بافت­ کبد بیان شود. سپس به توضیح نقش التهاب در بیماری سرطان و فاکتورهای التهابی و دستگاه­های رشدی مورد نظر پژوهش، پرداخته شد. در نهایت به برخی از پژوهش­های انجام شده در خصوص دوکسوروبیسین با تمرکز بر حوزه­های ورزشی و غیر ورزشی، در بافت کبد اشاره می­شود.

2-2.  مبانی نظری پژوهش

2-2-1. آنتراسایکلین­ها و تاریخچه

آنتراسیکلین­ها داروهای ضد سرطان هستند که برای درمان بسیاری از سرطان­ها از جمله لوسمی، لنفوم، پستان، رحم، تخمدان، و سرطان ریه مورد استفاده قرار می­گیرند. از میان موثرترین داروهای ضد سرطان، آنتراسیکلین ها توسعه بیشتری پیدا کرده­اند و در مقابل دیگر راه­های درمان بیماری سرطان، بسیار موثرتر بوده­اند. متاسفانه این داروها اثرات نامطلوبی دارند که استفاده از آن­ها را محدود کرده است و از مهم­ترین عوارض آن سمیت قلبی است. اولین آنتراسایکلین کشف شده دئونوروبیسین^[1](DNR) بود که از نوعی آکتینو باکتری به نام استرپتومایسس پئوستیوس به دست آمد. در مدت کوتاهی پس از آن، استفاده از دوکسوروبیسین(DOX) توسعه پیدا کرد و به دنبال آن ترکیبات دیگری ساخته شدند و مورد استفاده بالینی قرار گرفتند. (DOX) و(DNR) دارای بخش قندی و غیر قندی هستند. بخش غیر قندی  شامل یک حلقه تتراسایکلین و گروه مجاور کینون- هیدروکینون، و یک گروه متوکسی و یک زنجیره جانبی کوتاه گروه کربونیل است. بخش قندی، که دئونوزآمین نامیده می­شود، از اتصال پیوند گلیکوزیدی به یکی از حلقه­های متشکل از 3 آمینو-2،3،6- تریدئوکسی- ال-فاکوزیل تشکیل شده است. تنها تفاوت بین این دو مولکول در زنجیره جانبی می­باشد که در دوکسوروبیسین(DOX) به یک گروه الکل و در دئونوروبیسین(DNR) به یک گروه متیل متصل می شوند(شکل 2-1). با وجود استفاده گسترده از آنتراسایکلین­ها، آنها اثرات سوء چندجانبه ای ایجاد می­کنند که سمیت یکی از شناخته شده ترین این اثرات است]29[.

به عنوان مثال، اپی روبیسین^[2](EPI)  یک داروی آنتراسایکلین­ مورد استفاده در شیمی درمانی است  که می توان آن را در ترکیب با سایر داروها  برای درمان سرطان و جراحی به منظور برداشتن تومور مورد استفاده قرار داد. اپی روبیسین دارای آرایش­های مختلف فضایی از گروه هیدروکسیل در کربن شماره 4 از قند است که ممکن است برای حذف سریع آن و کاهش سمیت آن موثر باشد. بااین حال، جایگزینی دوکسوروبیسین(DOX) توسط اپی روبیسین (EPI) نمی­تواند خطرات مزمن سمیت قلبی را حذف نماید زیرا مانند سایر آنتراسایکلین­ها، اپی روبیسین با تاثیر بر روی رشته های DNA عمل میکند و باعث ایجاد مکانیسم­های پیچیده­ای می­شود که سنتز DNA و RNA را مهار می­کند. برخی از این مکانیسم­های اپی روبیسین شامل: شکسته شدن DNA توسط توپوایزومراز-2 و سپس مرگ سلول، اتصال به غشاء سلولی و پروتئین های پلاسما و منجر شدن به ایجاد ترکیباتی با اثرات سمی، تولید رادیکال های آزاد و منجر شدن به آسیب سلول و DNA می­باشد] 29،18 [.

 

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