1. 1/1/2015
Mohamed M. Sayed-Ahmed
PHL 425 Dr. Mohamed M. Sayed-Ahmed Topoisomerase Inhibitors and Multidrug Resistance
PHL 425

2. 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
17q P24

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. Topoisomerase I mechanism of action
TPT

10. 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.

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. 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

15. COMPETITIVE P-GLYCOPROTEIN BLOCKERS

16. NON-COMPETITIVE P-GLYCOPROTEIN BLOCKERS

17. 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