06a Topoisomerase Inhibitors Camarero

Question 1

What are the two prototype drugs of Topoisomerase II Inhibitors?

Answer 1

Antracyclines (Doxorubicin). Epipodophyllotoxins (Etoposide)

Question 2

What is the Topoisomerase I Inhibitor prototype drug?

Answer 2

Captothecins (Topotecan)

Question 3

What is Topoisomerase (TOP)?

Answer 3

They are essential for mammalian cells. TOP-mediated mechanism for relaxing supercoiled DNA

Question 4

What do TOP Inhibitors do?

Answer 4

Prevent relaxing DNA required for replication and transcription. Inhibition of TOP enzymes is cytotoxic for rapid dividing cells (cancer cells)

Question 5

What are the four independent modes of action of Anthracyclines (TOP II Inhibitor)?

Answer 5

Inhibit TOP II enzyme, preventing the relaxing of supercoiled DNA and thus blocking transcription and replication. Inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells. Create free oxygen radicals and superoxide that damage the DNA and cell membranes. Alkylation of DNA/RNA through reductive formation of a reactive quinone methide

Question 6

What are Anthracyclines used to treat?

Answer 6

A wide range of cancers, including leukemias, lymphomas, and breast, uterine, ovarian, and lung cancers

Question 7

How are Anthracyclines administered?

Answer 7

Orally or through IV (liposome formulation)

Question 8

How are Anthracyclines metabolized/eliminated?

Answer 8

Metabolized in the liver (oxidation and/or glucoronidation). Renal and biliary/fecal excretion

Question 9

What are the Anthracycline drugs?

Answer 9

Doxorubicin. Daunorubicin. Epirubicin

Question 10

What is the toxicity like with Anthracyclines?

Answer 10

Cardiotoxicity (heart damage, may be fatal). Vomiting. Total alopecia. Bone marrow suppression. These considerably limit their usefulness as antieoplasic agents

Question 11

What is Daunorubicin (an Anthracycline) used for?

Answer 11

Used primarily in the treatment of acute leukemias and lymphoma. It has also been used to treat neuroblastome

Question 12

How is Daunorubicin (an Anthracycline) administered?

Answer 12

Exclusively through intravenous administration. Causes severe necrosis if administered intramuscularly or subcutaneously. It should NEVER be administered intrathecally (into the spinal canal), since it will cause extensive damage to nervous system (may lead to death)

Question 13

How can the toxicity of Daunorubicin (an Anthracycline) be reduced?

Answer 13

When formulated as a liposome (DaunoXome). Liposomes are efficient vehicles for the delivery of drugs

Question 14

What are Epipodophyllotoxins (TOP II Inhibitor) used to treat?

Answer 14

Ewing’s sarcoma, lung cancer, testicular cancer, lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme

Question 15

What are the Epipodophyllotoxins used?

Answer 15

Etoposide. Teniposide

Question 16

How are Epipodophyllotoxins administered?

Answer 16

Orally (Etoposide) or by IV (Etoposide and Teniposide)

Question 17

What are the general characteristics of Epipodophyllotoxins?

Answer 17

Distribute widely through the body. Able to cross the BBB. Metabolized in the liver into less active metabolites. Renal and fecal excretion

Question 18

What is the MOA of Epipodophyllotoxins?

Answer 18

Blocks cells in the late S-G2 phase of the cell cycle through inhibition of TOP II. Stabilizes TOP II-DNA adducts resulting in DNA breaks

Question 19

What are the toxicities and ADRs associated with Epipodophyllotoxins?

Answer 19

N/V. Alopecia. Hematopoietic andlymphoid toxicity (infections, anemia, bleeding)

Question 20

What are Camptothecins (CPT)?

Answer 20

CPT is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme TOP I. CPT shows remarkable anticancer activity but also low solubility and severe side-effects

Question 21

What are the two Camptothecin (CPT) analogues used?

Answer 21

Irinotecan and Topotecan. They have improved water solubility, which have been approved as antieoplastic agents

Question 22

What is the MOA of Camptothecin (CPT) analogues?

Answer 22

They interfere the activity of TOP I by preventing religation of single-strand breaks and producing DNA damage

Question 23

What are Camptothecins (CPT) used to treat?

Answer 23

Metastatic ovarian cancer (Topotecan), colon and rectal cancer (Irinotecan)

Question 24

What are the toxicity and side-effects with Topotecan?

Answer 24

Neutropenia (low neutrophile count). Thrombocytopenia (low platelet count). Anemia

Question 25

What are the toxicity and side-effects with Irinotecan?

Answer 25

Severe diarrhea. Myelosuppression (infection and bleeding risks)

Question 26

What are the characteristics of Irinotecan?

Answer 26

A prodrug that is metabolized in vivo to an active TOP Inhibitor. It is also oxidized to APC and NPC

Question 27

In summary, what are the functions and cancer targets of Anthracyclines?

Answer 27

TOP II Inhibitor, DNA intercalator and crosslinker, generation of free and oxygen radicals; block DNA replication and transcription - breast, ovarian and testicle cancers, sarcoma, leukemia

Question 28

In summary, what are the functions and cancer targets of Epipodophyllotoxins?

Answer 28

Pure TOP II Inhibitor - Damage DNA through strand breaks - monocytic leukemia, testicular cancer, oat cell carcinoma of the lung

Question 29

In summary, what are the functions and cancer targets of Camptothecins?

Answer 29

TOP I Inhibitor - advanced breast cancer resulting in DNA damage - metastatic ovarian, colon, and rectal cancers