TOPOISOMERASE INHIBITORS and (Multidrug Resistance (MDR PHL 417

TOPOISOMERASE INHIBITORS 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 alpha TOPO II beta 170 kd 18o kd 17q21 3P24

Topoisomerase I (Live)

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.

TOPOISOMERASE I INHIBITORS TOPOTECAN IRINOTECAN COMPTOTHECIN (CPT 11) INTOPLICINE

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

Topotecan stabilises topoisomerase I-DNA cleavable complex

Topoisomerase I mechanism of action TPT

INTERACTION OF TOPO I AND 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.

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

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

P-GLYCOPROTEIN

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)

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

COMPETITIVE P-GLYCOPROTEIN BLOCKERS

NON-COMPETITIVE P-GLYCOPROTEIN BLOCKERS

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