06a Topoisomerase Inhibitors Camarero Flashcards Preview

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What are the two prototype drugs of Topoisomerase II Inhibitors?

Antracyclines (Doxorubicin). Epipodophyllotoxins (Etoposide)


What is the Topoisomerase I Inhibitor prototype drug?

Captothecins (Topotecan)


What is Topoisomerase (TOP)?

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


What do TOP Inhibitors do?

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


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

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


What are Anthracyclines used to treat?

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


How are Anthracyclines administered?

Orally or through IV (liposome formulation)


How are Anthracyclines metabolized/eliminated?

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


What are the Anthracycline drugs?

Doxorubicin. Daunorubicin. Epirubicin


What is the toxicity like with Anthracyclines?

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


What is Daunorubicin (an Anthracycline) used for?

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


How is Daunorubicin (an Anthracycline) administered?

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)


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

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


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

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


What are the Epipodophyllotoxins used?

Etoposide. Teniposide


How are Epipodophyllotoxins administered?

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


What are the general characteristics of Epipodophyllotoxins?

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


What is the MOA of Epipodophyllotoxins?

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


What are the toxicities and ADRs associated with Epipodophyllotoxins?

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


What are Camptothecins (CPT)?

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


What are the two Camptothecin (CPT) analogues used?

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


What is the MOA of Camptothecin (CPT) analogues?

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


What are Camptothecins (CPT) used to treat?

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


What are the toxicity and side-effects with Topotecan?

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


What are the toxicity and side-effects with Irinotecan?

Severe diarrhea. Myelosuppression (infection and bleeding risks)


What are the characteristics of Irinotecan?

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


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

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


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

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


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

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