Intercalating Agents, Tubulin Active, Topoisomerase Inhibitors

Describe the mechanism of action of the following:

• Topoisomerase inhibitors (Topotecan, Irinotecan, Etoposide, Teniposide)

Topoisomerase inhibitors are drugs that interfere with the function of topoisomerases, enzymes that help relieve strain in DNA during replication and transcription.

By stabilizing the DNA-topoisomerase complex, they prevent the re-ligation of the DNA strands, leading to cell death during the S-phase of the cell cycle.

Describe the mechanism of action of the following:

• Tubulin-active agents (Paclitaxel, Docetaxel, Vincristine, Vinblastine, Vinorelbine)

Vinica: binds to B-tubulin, blocking its association with a-tubulin arresting mitosis in metaphase

• tubulin dimers cannot form microtubulins

Taxanes: Bind to b-tubulin to promote and stabilize microtubule formation thus halting mitosis in metaphase

• microtubules cannot break down to tubulins

Describe the mechanism of action of the following:

• Anthracyclines and Anthracenediones (Doxorubicin, Daunorubicin, Idarubicin, Liposomal Doxorubicin Mitoxantrone)

Multimodal

1. intercalates with DNA preventing transcription and replication

2. inhibits topoisomerase II - preventing DNA re-ligation

3. generation of free radicals via iron interactions

Describe the mechanism of action of the following:

• Bleomycin

causes oxidative damage to nucleotides leading to DNA strand breaks

• Identify the COMMON and UNIQUE toxicities of these drugs, and how they can be mitigated, including

  • Relative cardiotoxicity of the anthracyclines and the effect of infusion rate and dexrazoxane

  • Relative neurotoxicities of the tubulin-active agents

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• Per-dose and lifetime dose limitations of…

  • Anthracyclines

  • Vincristine

  • Bleomycin

• Anthracyclines

  • daunorubicin - 800 mg/m2

  • Doxorubicin - 400 mg/m2 for rapid IV

  • Epirubicin - 900 mg/m2

  • Idarubicin 150 mg/m2

  • mitoxantrone - 160mg/m2

• Vincristine

• Bleomycin

  • lifetime dose 400 units total, >250 units/m2

• Dose adjustments for:

  • Renal or hepatic dysfunction

hepatic dysfunction

• dose reductions for Vincas

• dose reductions for taxanes

• dose reductions for anthracyclines and anthracenedione

Renal dysfunction

• topotecan (topoisomerase I inhibitors)

• Etoposide (topoisomerase II inhibitors)

• dose reduction in bleomycin

Dose adjustments for Progressive neuropathy

???

dose adjustments for Type I and Type II metabolizing enzyme polymorphisms (CYP, UGT)

irinotecan (prodrug) - topoisomerase I inhibitors

• activated to SN38 by carboxyesterases

• inactivated by CYP3A4 and UGT1A

Differences in the treatment of extravasations

• Anthracyclines

• Vincas

Anthracyclines

• cold compress

• antidote: dexrazoxane

Vincas

• hot compress

• antidote: hyaluronidase

Pre-treatment adjunctive medications for taxane hypersensitivity

• Docetaxel vs Paclitaxel

Docetaxel

• dexamethoasone 8 mg PO

Paclitaxel

• dexamethasone 20 mg PO

• diphenhydramine 50 mg IV

• famotidine 20 mg IV

Post-treatment adjunctive medications for Chemotherapy-induced neuropathy in Paclitaxel

• duloxetine - recommended

• gabapentin - reasonsable

Administration apparatus and infusion rate requirements for safety, tolerance, and formulation requirements

• Vincas

• Etoposide

• Paclitaxel

Vincas:

• can be fatal if administered intrathecal

• prepared in a small bag now with a “FATAL” sticker

Etoposide

• requires in-line filter

• oral F = 50%

Paclitaxel

• infused with a in-line filter and prepared with a non-PVC bag to prevent risk of prescription and adhesion to PVC bag

How does the treatment of acute diarrhea following irinotecan differ from chronic?

acute

• within 24 hrs of start on infusion due to direct ACh inhibition by irinotecan

• txt: atropin (anti-chol)

chronic

• 2-12 days after infusion due to SN-38 reactivation causing irritation and secretion in the GI tract

• txt: loperamide

How do the acute vs chronic dose-limiting toxicities of the anthracyclines differ?

acute

• myelosuppression

• mucositis and GI toxicity

• Vesicant

chronic

• cardiotoxicity (dose limiting)

• moderate-high emetogenciity (regimen dependent)

What factors increase the risk of cardiomyopathy in patients receiving anthracyclines?

• cumulative anthracycline dose

• cardiac involvement in the radiation field (chest and heart area)

• age (older »younger)

Why does bleomycin toxicity largely affect the lungs and skin?

Due to its metabolism pathway

• bleomycin is degraded by a hydrolase concentrated in the liver but that is deficient in the skin and lung (meaning accumulations occur)

What factors increase the risk of bleomycin pulmonary toxicity?

• exposures to high FiO2

• pre-existing lung disease

• older age at txt (>70yo)

• larger doses (limit to 30 units)

• cumulative dose >400 units total

• lung field radiation therapy