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Oxidative Stress: Implications for Cancer Therapy

Oxidative Stress: Implications for Cancer Therapy. Dr. Nasir Ali Afsar MBBS, M.Phil , Ph.D Senior Lecturer of Pharmacology Alfaisal University, Riyadh, KSA. What is Oxidative Stress?. An imbalance between the production of reactive radicals within a system and their disposal .

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Oxidative Stress: Implications for Cancer Therapy

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  1. Oxidative Stress:Implications for Cancer Therapy Dr. Nasir Ali AfsarMBBS, M.Phil, Ph.D Senior Lecturer of Pharmacology Alfaisal University, Riyadh, KSA.

  2. What is Oxidative Stress? • An imbalance between the productionof reactive radicals within a system and their disposal. http://image.rakuten.co.jp/create-book/cabinet/c06/big_25.jpg 10th SKMCH&RC Symposium, Lahore

  3. Normal Biological Oxidation-Reduction • Energy extraction from food • Nonspecific cytotoxic defense • Xenobiotic metabolism and disposition • Cell signaling 10th SKMCH&RC Symposium, Lahore

  4. Biochemical Implications Oxidative stress accumulates • Peroxides [O-O]-2: Macromolecule* damage • Free Radicals: Macromolecule damage • Superoxide (O2-) ions • Hydroxyl (OH) radical • Redox second messengers: fibrosis, aging *Macromolecule = proteins, lipids, DNA, RNA, carbohydrates. 10th SKMCH&RC Symposium, Lahore

  5. Important Sources of ROSs • Metabolic enzyme systems: • Mitochondria – Electron transport chain • Peroxisomes – Mixed function oxidases: Cyt P450 • Phagosome membrane – NADPH oxidases • Cellular membranes – Xanthine oxidase • Nitric oxide synthases 10th SKMCH&RC Symposium, Lahore

  6. Important Sources of ROSs • Irradiation • UV-light • Smoking • Pollution • Inflammation www.smokersrx.com/images/why2.jpg 10th SKMCH&RC Symposium, Lahore

  7. Important Antioxidant Systems • Superoxide dismutase and catalase • Glutathione Peroxidases, Glutathione S-Transferases and HMP-Shunt • Aldehyde dehydrogenases • Peroxidredoxins and sulfiredoxins • Antioxidant moeities – ascorbic acid, tocopherol, SH-compounds, ceruloplasmin etc. 10th SKMCH&RC Symposium, Lahore

  8. Antioxidant Defense http://www.drproctor.com/rev/84/84rev.htm 10th SKMCH&RC Symposium, Lahore

  9. Implications for Cancer Treatment • Majority of chemotherapeutic agents • produce oxidative stress in addition to their mode of action • affect macromolecules • are poorly selective for malignant tissue • induce apoptosis • Radiation energy facilitates generation of ROSs and thus produces oxidative stress 10th SKMCH&RC Symposium, Lahore

  10. Implications for Cancer Treatment • The antioxidant systems generally • enable absorption of chemical or radiation insult. • do not directly take part in drug metabolism. Exceptions exist, such as cyclophosphamide. 10th SKMCH&RC Symposium, Lahore

  11. Cyclophosphamide Metabolism CP Cyt P450 ALDH 4OH-CP (plasma) Carboxy-CP (inactive) Thick arrow = Major pathway ALDH = Aldehyde dehydrogenase CP = Cyclophosphamide GST = Glutathione S-transferase PM = Phosphoramide Mustard 4OH-CP = 4 hydroxy CP Shunt Pathway GST PM-GSH (inactive) PM (intracellular) 10th SKMCH&RC Symposium, Lahore

  12. ALDH Genotype and Effect on Plasma 4OH-CP:CP • Increased shunting through ALDH leads to increased 4-OH-CP clearance (less 4OHCP:CP). • Poorer shunting through ALDH translates into greater 4OHCP:CP as well as adverse effects • Effects on chemotherapy successand patient survival ? 10th SKMCH&RC Symposium, Lahore

  13. ALDH Genotype and Effect on Plasma 4OH-CP:CP CP = Cyclophosphamide ALDH = Aldehyde dehydrogenase *1 = Wild-type or Normal allele *2 = Variant or Non-functional allele 10th SKMCH&RC Symposium, Lahore

  14. Adverse Effects of Chemotherapy • The cytotoxicity is mainly borne by rapidly dividing cells, including malignant cells, bone marrow, mucosae, skin, germinal epithelium. • Slowly proliferating cells accumulate mutations. 10th SKMCH&RC Symposium, Lahore

  15. Adverse Effects of Chemotherapy • Compromised antioxidant systems pose greater threat for adverse effects. • Example: loss of a single functional allele of GSTA1 predisposes to severe leukopenia among breast cancer patients on low dose cyclophosphamide. 10th SKMCH&RC Symposium, Lahore

  16. GST Genotype and Severity of Leukopenia TLC: Day 10 post-chemotherapy GST = Glutathione S-Transferase *A = Wild-type or Normal allele *B = Variant or Non-functional allele 20-11-2011 10th SKMCH&RC Symposium, Lahore

  17. Summary • Radiotherapy as well as majority of chemotherapy poses oxidative stress. • Compromised antioxidant systems predispose to greater adverse effects. • Possible role in effective management and toxicity prediction. 10th SKMCH&RC Symposium, Lahore

  18. Oxidative Stress: Implications for Cancer Therapy Thank you 10th SKMCH&RC Symposium, Lahore

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