TOPOISOMERASE INHIBITORS and Multidrug Resistance MDR PHL 417

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 18 o kd 17 q 21 3 P 24

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) • MDR 1 (P-glycoprotein) • MDR 2 • MDR 3 Resistance 2 - Multidrug Resistance Associated Protein (MRP) 3 - Lung Resistance Related Protein (LRP) 4 - Breast Cancer Resistance Protein (BCRP)

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