Conventional Chemo PCOL -(Topoisomerase inhibitors)

4 classes of Topoisomerase Inhibitors

1. Anthracyclines (Doxorubicin)

2. Epipodophyllotixins (Etoposide)

3. Camptothecins (irinotecan)

4. Other (bleomycin)

TOPO inhibitors GENERAL MOA

• They all have VARYING cell-cycle specificity

• What do Topoisomerases do?

  • They MAINTAIN DNA structure during replication and transcription —→ relieves strain during the DNA unwinding by resealing any strand breaks

• MOA

  • If you interfere with Topo I or Topo II —→ DNA strands break —→ Inhibition of DNA synthesis and repair

TOPO inhibitors CLASS-wide toxicities

1. Myelosuppression

2. Alopecia

3. Infertility

4. Vesicants/Irritants (anthracyclines (Doxo))

   1. from central line IV

   2. Monitor for extravasation

Anthracyclines MOA (Doxorubicin)

1. CELL-CYCLE NON-SPECIFIC

2. MOA

   1. Inhibits TOPO II

   2. Intercalates between the DNA base pairs —→ Inhibits DNA/RNA synthesis

   3. They produce a reactive oxygen species + free radicals —→ cleaves DNA and damages membranes

Anthracyclines (doxorubicin) Common toxicities AND RBS AE’s

Common

• Discoloration of body fluids (RED)

• CINV (chemo-induced Nausea/Vomiting)

RBS

• Cardiotoxicity (Acute, early, late)

  • late stage is DOSE-dependent

  • Prevent by not giving more than max dose = MAX LIFETIME DOSE IS 450 mg/m2

• Vesicant

  • Apply cold and consider Dexrazoxane

• Secondary Malignancies (MDS/ AML)

EpipodoPhyllotoxins (Etoposide) MOA, Common toxicities, RBS

• Cell-cycle SPECIFIC —→ S AND G2 phase

• MOA

  • Topo II inhibitor

  • Intercalate between DNA base pairs - inhibits DNA/RNA synthesis

  • May Inhibit mitochondrial transport at the NADH level

Common

• Infusion-related HYPOtension

RBS

• Anaphylaxis/hypersensitivity (can switch to Etoposide PHOSPHATE) if so

Camptothecins (Irinotecan) MOA + toxicity

• Cell-cycle SPECIFIC —→ S phase

• MOA

  • Topo I inhibitor

  • Binds reversibly to Topo-I-DNA complex —→ prevents cleaved DNA strand form relegating —→ Accumulation of complexes and double strand DNA breaks

Select toxicity (I Run To The Can)

• Diarrhea! —→ Active metabolite SN-38 causes it

• Early Diarrhea - 51% // late diarrhea - 88 %

Antitumor Antibiotic (Bleomycin) MOA, toxicity, RBS

• Cell cycle SPECIFIC (G2 and M)

• MOA

  • Glycopeptide ABX

  • Binds to Guanine-cytosine portion of DNA —→ causes single AND double strand breaks —→ inhibits DNA/RNA synthesis

  • Metabolized by bleomycin hydrolase (high concentration of this in blood)

Common

• Skin HYPERPigmentation

RBS

• Pulmonary toxicity (pneumonia, fibrosis)

• Hypersensitivity (anaphylaxis)