Hem/Onc Exam 3: Lapinsky Anti-Mitotic Agents

mitosis: the process by which a cell divides its duplicated ___ into 2 identical sets, producing 2 genetically identical nuclei

chromosomes

mitotic spindle: a dynamic football-shaped structure made of ___ that forms during mitosis to separate duplicated chromosomes into 2 daughter cells

microtubules

2 clinically relevant anti-mitotic agents used in the treatment of cancer:

1. ___ ___

2. ___

vinca alkaloids, taxanes

what is it?

tubulin: a protein

microtubules: hollow, cylindrical polymers of ___

tubulin

primary role?

tubulin: building block to make ____

microtubules: structural and ___ machinery

microtubules, functional

assembly?

tubulin: tubulin dimers ___

microtubules: ___ and ___ dynamically

polymerize, grow, shrink

cell division?

tubulin: ____ for mitotic spindle formation

microtubules: forms the mitotic spindle

subunits

neuronal function?

tubulin: supplies subunits for neuronal microtubules

microtubules: supports ___ ___ and neuronal structure

axonal transport

concerning anti-mitotics

tubulin: ___ ___ of vinca alkaloids and taxanes

microtubules: dynamic equilibrium that is disrupted by vinca alkaloids and taxanes

drug target

Vinca Alkaloids must know drugs?

vincristine, vinblastine

Taxanes must know drugs?

paclitaxel, docetaxel, nab-paclitaxel

molecular target?

Vinca Alkaloids: β-tubulin within an α,β-____ ____

tubulin heterodimer

molecular target?

Taxanes: β-tubulin within a ____

microtubule

MOA?

Vinca Alkaloids: inhibit the ___ of a microtubule

Taxanes: inhibit the ___ of a microtubule

assembly, disassembly

Effect on microtubule structure?

Vinca Alkaloids: too ___ assembly

Taxanes: "___"

little, hyperstabilized

Effect on mitosis?

Vinca Alkaloids: prevent ___ of the mitotic spindle

formation

Effect on mitosis?

Taxanes: disrupt mitotic spindle ___

dyamics

Cell Cycle Specificity?

Vinca Alkaloids: __ phase

Taxanes: ___ phase

M, M

Major toxicities

Vinca Alkaloids: ___ ___ and ___

peripheral neuropathy, myelosuppression

Major toxicities

Taxanes: ___ ___ and ___

peripheral neuropathy, myelosuppression

Why do Vinca Alkaloids notoriously cause peripheral neuropathy?

by disrupting microtubule assembly → disrupting ___ __ → causing neuronal dysfunction

axonal transport

peripheral neuropathy symptoms

1. numbness/tingling in hands/feet

2. general weakness/loss of reflexes

3. ___ (common) and potential ___ ___ from autonomic neuropathy

constipation, paralytic ileus

What is the single most important administration warning concerning any Vinca Alkaloid?

for IV use only, fatal if given other routes

Vinca Alkaloids should NEVER be administered ____ (ie directly into cerebrospinal fluid) because this can cause fatal neurologic injury

intrathecally

Vinca Alkaloids

-should be administered IV only as ___-soluble sulfate salts

water

Vinca Alkaloids are notorious vesicants. Manage with ___ and a __ compress

hyaluronidase, warm

Taxanes

-unlike vinca alkaloids, these agents are notoriously ___ in almost everything!

insoluble

Formulation of Paclitaxel: ____ ___ + ____

cremophor EL, ethanol

Formulation of Docetaxel: ____ ___

polysorbate 80

Formulation of Nab-paclitaxel: ____ ___-___ (reconstituted with NS)

nanoparticle albumin-bound

Hypersensitivity risk to formulation?

Paclitaxel + Docetaxel: ____

Nab-paclitaxel: ____ !

significant, lower

Premedicate prior to IV?

Paclitaxel + Docetaxel: yes, with corticosteroid +/- H1/H2 blocker

Nab-paclitaxel: ____ !

no

Distinctive toxicity of Docetaxel:

-can cause ___ ___ (edema/pulmonary edema) due to increased capillary permeability

fluid retention

a select drug combo involving taxanes combines ____ with _____ (Taxol)

cisplatin, paclitaxel

drug target

cisplatin: ____

paclitaxel: β-tubulin within ____

DNA, microtubules

cell cycle specificity?

cisplatin: ____

paclitaxel: ___

CCNS, CCS

recruitment schedule? (more effective)

cisplatin: give ____

paclitaxel: give ___

first, second

nonrecruitment schedule (safer, used in practice)

cisplatin: give ____

paclitaxel: give ___

second, first

Why give paclitaxel first, cisplatin second?

-cisplatin can impair the hepatic ___ and biliary ___ of paclitaxel by damaging hepatocytes and altering CYP enzyme function

metabolism, excretion

Why give taxol first, cisplatin second?

-giving cisplatin first would lead to decreased paclitaxel metabolism/clearance, and therefore increased paclitaxel ____

toxicity

Why give taxol first, cisplatin second?

-paclitaxel toxicity manifests as cumulative ___ ___ suppression and a higher ___ risk

bone marrow, neutropenia

Why give taxol first, cisplatin second?

-when paclitaxel is given before cisplatin, bone marrow toxicity is less severe due to ___ paclitaxel metabolism/excretion

preserved

a select drug combo involving taxanes combines ____ (Xeloda) with _____ (Taxol)

capecitabine, paclitaxel

class

capecitabine: pyrimidine ___-___

paclitaxel: ___-____

anti-metabolite, anti-mitotic

CCS- phase inhibited

capecitabine: __ phase

paclitaxel: ___ phase

S, M

MOA

capecitabine: an oral prodrug of 5-FU that is activated via ___ ___ (TP)

paclitaxel: ___ microtubules, which leads to mitotic arrest in the M phase and triggers cancer cell apoptosis

thymidine phosphorylase, hyperstabilizes

Effect on cancer cells?

capecitabine: 5-FdUMP inhibits __ __ in the cancer cell

paclitaxel: inhibits further cancer cell ___ and induces mitotic cancer cell death

DNA synthesis, division

paclitaxel increases the expression/amount of ___ ___ (TP) in cancer cells), therefore enhancing capecitabine local ____ and therefore enhancing tumor killing

thymidine phosphorylase, conversion

Giving capecitabine concurrent with paclitaxel takes advantage of this biochemical environment, thus improving select prodrug activation of capecitabine in cancer cells more than in normal cells (increases "___ ___")

selective toxicity

Florida State University's development of _____ of taxol made large-scale production of the drug possible (previously had to get from pacific yew trees that took 200 years to grow)

semisynthesis