Pharmacology Iii - Topoisomerase Inhibitors

Front 1

Discuss the different subgroups of Topoisomerase Inhibitors and the drugs associated with those groups.

Back 1

Topoisomerase Inhibitors are divided into two main classes --> Topoisomerase I and II inhibitors.

Topoisomerase I Inhibitors (non-intercalating) include Topotecan and Irinotecan

Front 2

Continuation of last answer

Back 2

Topo II Inhibitors are split into non-intercalating (Epipodophyllotoxins) and interacalating agents (Anthracyclines)

Non-intercalating agents include Etoposide and Teniposide

Intercalating agents include Doxorubicin, Daunorubicin, Idarubicin, Epirubicin

Front 3

Topoisomerases are enzymes that mediate DNA unwinding from a supercoiled state by cutting one or both strands and re-ligating them. What is the function of Topo I vs Topo II?

Back 3

Topo I cuts a single strand

Topo II cuts a double strand

Front 4

How do inhibitors of Topoisomerase work?

Back 4

They allow the cutting of the DNA, but prevent the re-ligation. Cleaved DNA fragments accumulate in the cell eventually causing cell death.

Front 5

Topotecan and Irinotecan are Topoisomerase I Inhibitors that bind to the Topoisomerase - DNA complex and inhibit re-ligation. What is Topotecan indicated for? What phase specifically does it inhibit?

Back 5

NSCLC
Ovarian Cancer

S Phase

**IV > PO in survival and side effects

Front 6

Chemotherapeutic agents have common side effects due to the inhibition of rapidly dividing cells. Name these side effects.

Back 6

Alopecia
GI - N/V/D
Hepatic Toxicity
Mucosal Damage
Myelosuppression
Infertility/Teratogenicity

Front 7

What is Irinotecan indicated for? What phase does is inhibit specifically?

Back 7

Colorectal Cancer
Rectal Cancer

S phase

Front 8

Discuss the importance of Irinotecan's metabolism.

Back 8

Irinotecan is a prodrug. It is converted to a compound called SN-38 in the liver which is 1000 times more potent than the initial form of the drug.
CYP3A enzymes inactivate Irinotecan, where Carboxyesterases activate the drug.
SN-38 is eventually inactivated in liver to SN-38 G and is excreted in the bile.

Front 9

What is UGT1A1? What is its importance?

Back 9

This is the enzyme that inactivates SN-38. Some patients have a mutated form and upon administration of Irinotecan will suffer from severe neutropenia as a result as SN-38 levels are increased.

Front 10

What enzyme reactivates SN-38 from SN-38 G? What is the significance of this?

Back 10

Bacterial enzyme in the GI tract called Beta-glucuronidase
This causes serious life threatening/late onset diarrhea.

Front 11

Describe the resistance associated with CPT analogs like Irinotecan and Topotecan.

Back 11

An overexpression of MDR-1 occurs.
This is a p-glycoprotein efflux pump that pumps the drug out of the cell.
Impaired drug activation by carboxyesterases
Overexpression of survival genes
Reduced Topoisomerase activity
Subcellular distribution - failure to localize to the nuceloli (site of action of drug)

Front 12

Etoposide and Teniposide are the two Epipodophyllotoxins. They are Topo II Inhibitors and are non-intercalating. What is the indication for Etoposide?

Back 12

Testicular cancer
Lung cancer

Front 13

What specific stage of the cell cycle does this drug inhibit?
What enzyme metabolizes these drugs?

Back 13

S phase
G2 phase

CYP3A4

Front 14

What is notable about the administration of these agents?

Back 14

They are poorly soluble and need to be administered with a solvent

Front 15

What does the inclusion of a solvent cause?

Back 15

Hypersensitivity reactions

Front 16

The topoisomerase II (Intercalating) Inhibitors include Doxorubicin, Daunorubicin, Idarubicin, Epirubicin. What is the difference in MOA between these agents and Etoposide and Teniposide?

Back 16

Topo II (Epipodophyllotoxins) bind to the Topo-DNA complex

Topo II (Anthracyclines) directly intercalate the DNA, inhibiting topoisomerase II. Again, strand breakage is not inhibited, but re-ligation.

***Anthracyclines also creative reactive oxygen species, but this is NOT part of their antitumor activity. Instead, this contributes to cardiac toxicity

Front 17

What is the major toxicity for anthracycles?
What specific cell cycle phase do they inhibit?

Back 17

Cardiac Toxicity - Congestive Heart Failure
Tissue Necrosis

Non-specific in terms of cell cycle

Front 18

Why are iron chelators used with anthracyclines?

Back 18

To scavenge cardiotoxic hydroxyl radicals

Front 19

What is the indication for Doxorubicin?

Back 19

Many different cancers ALL, AML, breast, ovarian, bladder, thyroid and more

Front 20

What is Doxil?

Back 20

Doxorubicin encapsulated in a STEALTH Liposome.
There is a substance on the surface of the liposome that makes it less detectable to the immune system and increases the drugs time circulating in the blood stream.
This doesn't increase drug efficacy, but does reduce toxicity and dose needed.