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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
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)
• MDR2
• MDR3
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