Topoisomerase & Mitosis Inhibitors Flashcards
Topoisomerase I
reduces torsional stress of supercoiled DNA –> binds and creates single strand break, and then religates the break
Topoisomerase II
reduces torsional stress of supercoiled DNA –> binds and creates DOUBLE strand break, and then religates the break
Topoisomerase I Inhibitors [drug]
Irinotecan
Irinotecan [MOA]
blocks RELIGATION mechanism of topoisomerase I
Irinotecan [active form]
SN-38
Irinotecan [PK]
CYp3A-mediated metabolism to inactive metabolite
Glucuronidation:
More=LESS risk for severe diarrhea
Less=increase severity of neutropenia
Irinotecan [Mechanisms of Resistance]
- Enhanced Export
- Lose activation of prodrug – increased CYP3A = LESS active drug
- Increased glucourinodination (metabolism)
Topoisomerase II Inhibitors [drugs]
Anthracyclines –
Doxorubicin
Daunorubicin
Anthracyclines [MOA]
- Intercalation
- Generate free radicals
- Inhibition of Topoisomerase II
Anthracyclines [PK]
DO NOT CROSS BBB
ALL of the drugs rapidly enter heart, lungs, kidney, liver & spleen
Metabolized by the liver
Anthracyclines [Mechanisms of Resistance]
- Enhanced expression of P-glycoprotein
- Mutations in Topoisomerase II
- Enhanced DNA repair mechanism
Bleomycin [ADE]
Pulmonary Fibrosis
Mitosis Inhibitors [drugs]
Taxanes: paclitaxel, nab-paclitaxel, docetaxel
Vinca Alkaloids: vincristine, vinblastine, vinorelbine
Vinca Alkaloids [MOA]
inhibit microtubule polymerization via B-tubulin binding
microtubules dissolve & form into crystals
Vinca Alkaloids [Mechanisms of Resistance]
- Increased P-glycoprotein expression
2. mutations in B tubulin
