الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
 |  | from | 193 |  |  |
| | | from | 193 | | |
Abstract
Methotrexate Is A Folate Antagonist Used For The Treatment Of A Wide Range Of Diseases where It Is Used In Large Doses For The Treatment Of Malignant Conditions In Both Children And Adults And In Low Doses For Treatment Of Non-Malignant Conditions.
Hepatic And Renal Intoxication By MTX Are Considered As Reasons That Retard Its Clinical Use. Therefore, The Present Study Was Conducted To Ameliorate These Toxicities By Natural Drugs; BBR, DADS And UMB As Well As To Be An Attempt For Enhancing MTX Cytotoxic Activity In Vitro Using Some Cancer Cell Lines.
I. In-Vivo Study:
For This Purpose, Sixty-Four Adult Male Albino Rats Were Categorized Randomly Into Eight Groups Of Eight Rats Each.
The 1st Group: Control group Received Vehicle Only.
The 2nd Group: Administered BBR (50 Mg/Kg/Day P.O) Daily For 10 Consecutive Days.
The 3rd Group: Administered DADS (50 Mg/Kg/Day P.O) Daily For 10 Consecutive Days.
The 4th Group: Administered UMB (30 Mg/Kg/Day P.O) Daily For 10 Consecutive Days.
The 5th Group: Administered MTX (20 Mg/Kg/Day As A Single Dose) I.P.
The 6th Group: Administered BBR Daily For 5 Consecutive Days Before MTX Treatment And 5 Days After.
The 7th Group: Administered DADS Daily For 5 Consecutive Days Before MTX Treatment And 5 Days After.
The 8th Group: Administered UMB Daily For 5 Consecutive Days Before MTX Treatment And 5 Days After.
Twenty-Four Hours After The Last Dose Of Each Treatment, Rats Were Anesthetized With Ketamine (100 Mg/Kg) By I.P. Injection.
II. In-Vitro Studies:
In The Current Study, In-Vitro Cytotoxic Activity Were Done On Human Colon Cancer; Caco-2 Cells, Human Hepatic Cancer; Hepg2 Cells And Human Breast Cancer; Mcf-7 Cells. The Anti-Cancer Efficacy Of BBR, DADS, UMB And Their Combination With MTX In Vitro Were Done Using MTT Assay.
The Main Findings Of The Present Study Can Be Summarized As Follows:
In-Vivo Studies:
1. Effect On Liver Function Tests:
o MTX Caused A Significant Elevation In Serum Levels Of ALT, AST, ALP And LDH As Compared To The Normal Control Group.
o Co-Administration Of BBR, DADS And UMB With MTX Resulted In A Significant Decrease In Serum Levels Of ALT, AST, ALP And LDH In Comparison With MTX-Treated Group.
2. Effect On Kidney Function Tests:
o Methotrexate Caused A Significant Elevation In The Serum Creatinine And Urea Levels As Compared To The Normal Control Group.
o Co-Administration Of BBR, DADS And UMB With MTX Significantly Attenuated The MTX-Induced Elevations In Serum Creatinine And Urea Levels As Compared To MTX-Treated Rats.
3. Effect On Oxidative Stress Biomarkers And Anti-Oxidant Enzymes Activity:
o Methotrexate Significantly Decreased Hepatic And Renal Reduced GSH Content, SOD Activity And Nrf-2 Expression Level. While Significantly Increased Hepatic And Renal MDA And NO2- Contents As Well As Keap-1 Expression Level With Respect To Control Group.
o Treatment With BBR, DADS And UMB In Line With MTX Significantly Increased Reduced GSH Content, SOD Activity And Nrf-2 Expression Level Meanwhile Produced A Significant Decrease In Both MDA, NO2- Contents And Keap-1 Expression Level As Compared To MTX-Treated Group.
4. Effect On Inflammatory Biomarkers:
o MTX Significantly Elevated Hepatic And Renal P38MAPK And NF-Κb Expression Levels As Compared To The Normal Control Group.
o Treatment With BBR, DADS And UMB Resulted In A Significant Decrease In MTX-Induced Increase In Hepatic And Renal P38MAPK And NF-Κb Expression Levels In Comparison With MTX-Treated Group.
5. Effect On Apoptosis:
o The Immunohistochemical Investigation Of Bcl-2, Bax And Caspase-3 Showed Weak Expression Of Bcl-2 And Strong Expression Of Bax And Caspase-3 In The Liver And Kidney Tissues Of MTX-Treated Rats As Compared To Sections Of Normal Control Rats.
o Administration Of BBR, DADS And UMB Markedly Alleviated The Changes Induced By MTX Through Producing Strong Expression Of Bcl-2 While Producing Weak Expression Of Both Bax And Caspase-3 As Compared To MTX-Treated Group.
6. Histopathological Examination Of Both Liver And Kidney:
o The Histopathological Examination Confirmed The Biochemical Investigations.
o Sever Histopathological Examination By MTX Administration For Liver And Kidney Tissues
o Co-Administration Of BBR, DADS And UMB With MTX Resulted In Significant Improvement In The Histopathology Of Liver And Kidney Sections Which Confirmed The Ability Of BBR, DADS And UMB To Protect Liver And Kidney Tissues Against These Injuries.
II. In Vitro Studies
Enhancement Of Anti-Tumor Efficacy Of MTX By BBR, DADS Or UMB Using Some Cancer Cell Lines.
Co-Treatment Of MTX With BBR, DADS And UMB Significantly Enhanced The Growth Inhibition For All Cell Lines Of Investigation, As Indicated By Markedly Decreased IC50 Values Of MTX.
from The Previous Findings It Could Be Concluded That:
o Co-Administration Of BBR, DADS And UMB With MTX Protect The Hepatic And Renal Tissues Via Regulation Of Redox-Sensitive Pathways; P38MAPK/NF-Kb, Nrf-2/Keap-1 In Addition Apoptosis Signaling Pathways Through Enhancement Of The Anti-Oxidant Status Of Liver And Kidney Via Nrf-2 Activation, Inhibition Of NF-Κb With Subsequent Inhibition Of Inflammatory Cytokines. These Besides Reduction Of Apoptosis Through Control Of Pro-Apoptotic, Anti-Apoptotic And Apoptotic Proteins Protect Liver And Kidney Against MTX Toxicity.
o Chemotherapeutic Combination Of BBR, DADS And UMB With MTX Is Of Great Synergism Using Caco-2, Hepg2 And Mcf-7 Cells.
Therefore, BBR, DADS And UMB Could Be A Potential Source Of Therapeutic Use As An Adjunct In Cancer Chemotherapy In order To Reduce The Large Dose Of MTX And Hence Its Toxic Adverse Effects As Well As In Combination With MTX In Chemotherapy Protocols.