Mitosis Inhibitors (MC) - Block 4 Flashcards by Hannah Lapos

What are Nonionic surfactant formulations used to dissolve very lipophillic drugs? Why?

Cremohor EL/Kolliphor EL: molecules resemble nonionic block copolymers -> activate proteins of immune responses

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What is the MOA of mitosis inhibitors?

Inhibits changes in microtubular structure -> mitotic arrest and apoptosis

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What occurs during cell division?

Altenation of polymerization (tubular elongation) and depolymerization (tubular shortening)

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What is the MOA of taxanes?

Bind to polymerized b-tubulin -> promoting polymerization preventing depolymerization
* Formation of asters due to extensive polymerization

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What phase do taxanes work best?

M phase

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What is the major mechanism of resistance towards taxanes?

PgP substrate

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ADR of taxanes?

Myelosuppression

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How do you reduce the hypersensitivity risk of paclitaxel?

Administer in vehicle of 50% alcohol/50% Cremophor EL due to low water solubility
Pretreat with antihistamines and corticosteroids due to surfactant formulation

Very heavily protein bound -> give abumin bound formulation

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ADR and DDI of paclitaxel?

ADR: Category D teratogen
DDI: Metabolized by CYP2C8

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How is docetaxel an improvement of pacitaxel?

Better water solubility -> can give in polysorbate 80 (less hypersensitivity than Cremophor) -> pretreat with corticosteroids

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What is better about carbazitaxel?

Better water solubulity -> give in polysorbate 80
* Dimethoxy analog (metabolite) of docetaxel -> lowers affintiy for PgP (sustained retention in tumor cells and better BBB penetration)

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ADR of carbazitaxel?

Diarrhea due to accumulation in enterocytes (doesn’t not get pumped out by Pgp)

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What is the major issue with taxans? What drug class was developed to overcome those problems?

Water solubilty and Pgp efflux -> epothilones

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Binding of epothilones?

Same as taxanes (polymerized b-tubulin to promote polymerization)

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Looking at the structure what are the properties of this epothilone?

Ixabepilone is very lipophilic and still requires Cremophor EL for administration

Not as different from taxanes

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What is the MOA of vinca alkaloids?

Inhibits polymerization (promoting depolymerization) binding at site on b-tubulin

Works in M phase

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Describe the structure of vinca alkaloids?

Ionizable amines - given as water soluble salts

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Metabolism of vinca alkaloids?

Undergoes O-deacylation to metabolites equal or more active than parent drugs

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ADR of vinca alkaloids?

Severe vesicants (necrosis) -> cold exacerbates tissue destruction therefore you should apply heat instead

All category D teratogens

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What vina is the least lipophilic but longest half life?

Vincristine (more prolonged tumor cell exposure)

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What is the major dose-limiting ADR?

Peripheral neuropathy
Lacks myelosupprssion

DDI if mitomycin -> delayed pulmonary toxicity

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Describe the structure of vinblastine?

Increased lipophilicity due to NCh3 replacing formyl group

What is the dose-limiting ADR of vinblastine?

Leukopenia (does cause myelosuppression)

What is the only venca that doesn’t cause myelosuppression?

Vincristine

What is the major ADR of vinorelbine?

Granulocytopenia and monitor for respiratory distress

What is the mechanism of topoisomerases?

**II:** cleaves dsDNA **I:** cleaves ssDNA

What is the mechanism of topoisomerase poisons?

Stimulates DNA cleavage but inhibits the DNA resealing activity -> irreversibly damaged DNA and no replication

What type of poison is epipodophyllotoxins

TopIIa

Where do epipodo target on the cell cycle

S and early G2 phase

Metabolism of epipodos?

CYP3A4

ADR of epipodos?

Mucositis, myelosuppression, Category D

What are the problems with epipodo?

Very water insoluble -> need solubility ehancers (Kolliphor EL) * Hypersensitivity rx (hypotension, thrombophlebitis) -> coadminister with epinephrine, antihistamines, and corticosteroids

How can epipodo become carcinogenic?

Reactive orthoquinone can promote topoisomerase-mediated DNA cleavage -> can cause translocation -> therapy-induced acute myeloid leukemia in children

What is the purpose for etoposide formulated with phosphate?

Phosphate ester analog -> water solubility (prodrug) and phosphate is removed in plasma

DDI of etoposides?

Organoplatinum

How does teniposide change the PK property compared to other epipodo?

More lipophilic and less soluble -> greater cellular uptake and more potent * More protein binding -> longer half-life * Likes to the precipitate

What is the natural antagonists camptothecins mimic?

Camptothecin

Looking at the structure what is the mechanism of this drug?

Flat ring system -> easy intercalation at site of cleavage (like DNA base)

What is the source of instability of camptothecins?

Lactones easily open and cleave * Hydrolyzed lactone (inactive) in equilibrium with intact lactone (active) -> bindign to pp leads to a shift towards more intact and active lactone * Lipophilic and acidic drugs increase bind to PP

What type of poison is camptothecins?

TopI * Works in S phase

ADR of camptothecins?

Myelosuppression

What dids irinotecan more potency?

1. More lipophilic and binds to PP 2. Prodrug: basic side chain (amine) is removed making it more lipophilic

What is the active form of iromptecan?

Needs phenol for activity

Metabolism of irinotecan?

Glucoronidation by UGTs (genetic variations can lead to toxicity)

ADRs of irinotecan?

**Delayed diarrhea** (dose-limiting) -> loperamide **Acute diarrhea:** anticholigeric tx

How does topotecan differ from irinotecan?

* Not a prodrug -> basic chain remains intact (phenol) * Less serum protein binding -> more hydrolysis (opening) of lactone because charged amine stays (less activity)

Why was topotecan developed if it hasless activity?

No toxicty with UGT polymorphisms

What is the MOA of demethylators?

Inhibits DNA methylation on genes respnsible for defferentiation and growth -> selectively killing cells that stopped responding to cellular proliferation control processes

Why are DNA demethylators given as prodrugs

Incorporated into DNA in place of cytidine or guanin -> irreversibly inhibit DNA methyltransferase

ADR of DNA demthylators

Anemia, neutropenia, thrombocytopenia

In order to have activity what does a DNA methyltransferase nhibitor need to have?

Undergo phosphorylation

What makes nelarabine an unique DNA methyltransferase inhibitor? ADR of nelarabine?

Can be metabolized to guanine/xanthine/urate * Give allopurinol (XOI) to hydrate and basify urine to reduce hyperuricemia **ADR:** severe, irreversible neurologic sx

Toxicity of azacitidine

Renal

Types of DNA methyltransferase inhibitors?

1. Azacitidine 2. Decitabine 3. Nelarabine