TOPOISOMERASE INHIBITORS and ( Multidrug Resistance (MDR PHL 417

1. TOPOISOMERASE INHIBITORSand (Multidrug Resistance (MDRPHL 417

2. Role of Topoisomerases (TOPO) • TOPOISOMERASES induce TRANSIENT BREAK in single strand (TOPO I) and double stands (TOPO II) and RESEALING. • Topoisomerase I : Swiveling DNA into 2 single strands which is important for transcription. • Topoisomerase II: Allow the passage of one segment of DNA-double strand through a temporary gate in other segment. Two types of TOPO II: TOPO II alphaTOPO II beta 170 kd 18o kd 17q21 3P24 TOPOISOMERASE INHIBITORS

3. Topoisomerase I (Live)

4. MECHANISM OF ACTION OF TOPOISOMERASE INHIBITORS 1- It inhibits the cycle (break and resealing) of TOPO at the DNA break point. 2- It inhibits DNA closing or resealing reaction by forming stable cleavable-TOPO-DNA complex. 3- It forms indirect protein-associated single and double strand break.

6. TOPOISOMERASE I INHIBITORS • TOPOTECAN • IRINOTECAN • COMPTOTHECIN (CPT 11) • INTOPLICINE

7. TOPOISOMERASE II INHIBITORS • 1- EPIPODOPHLLYOTOXINS - Etoposid (VP-16) - Teniposide (NM-26) • 2- ANTHRACYCLINES • Doxorubicin • Daunorubicin • Mitoxantrone • Idarubicin

8. Topotecan stabilises topoisomerase I-DNA cleavable complex

9. TPT Topoisomerase I mechanism of action

10. INTERACTION OF TOPO IAND TOPO II INHIBITORS 1- Simultaneous administration of TOPO I and TOPO II inhibitors leads to antagonism and decrease in cytotoxicity because both TOPO I and TOPO II have base specificity and may competes with each other for cleavable sites. 2- Sequential administration of TOPO I and TOPO II inhibitors leads to synergistic cytotoxicity.

11. RESISTANCE TO TOPOISOMERASE INHIBITORS 1- Altered Topoisomerase 2- Multidrug Resistance (MDR)

12. Multidrug Resistance (MDR) 1- Cross Resistance to many structurally unrelated anticancer drugs. 2- Intrinsic before exposure to chemotherapy. 3- Acquired after exposure to chemotherapy. 4- Caused by overexpression of FOUR MDR genes. 5- P-Glycoprotein is the most studied MDR protein. 6- P-glycoprotein acts as ATP-consuming pump that stimulate the efflux of cytotoxic drugs outside the cell

13. P-GLYCOPROTEIN

14. Genes Involved in MDR 1- Multidrug Resistance (MDR) • MDR1 (P-glycoprotein) Resistance • MDR2 • MDR3 2- Multidrug Resistance Associated Protein (MRP) 3- Lung Resistance Related Protein (LRP) 4- Breast Cancer Resistance Protein (BCRP)

15. MDR AGONISTS 1- Anthracyclines 2-Anthracenes • Doxorubicin - Mitoxantrone • Daunorubicin - Bisantrene • Epirubicin 3- Vinca Alkaloids 4- Epipodophyllotoxins Vinblastine Etoposide (VP-16) • Vincristine Teniposide (VM-26) • Vindesine • Vinorelbine 5- Topoisomerase Inhibitors 6- Taxanes Topotecan Paclitaxel Campttothecin Docetaxel

16. COMPETITIVE P-GLYCOPROTEIN BLOCKERS

17. NON-COMPETITIVE P-GLYCOPROTEIN BLOCKERS

18. MDR BLOCKERS • 1- Calcium channel blockers • Verapamil • Nifedipine • 2- Immunosuppressans • cyclosporin A • 3- Antiesterogen • Tamoxifen • 4- Calmodulin inhibitors • Trifluoperazine • Chlorpromazine • Prochlorperazine • 5- Antimalarial drugs • Quinine • 6- Antiarrhythmic drugs • Quinidine • Amiodarone