Exam 1 Lecture 5 Flashcards
What kind of drug is Mitomycin C? (MOA)
Dose limiting
Functions as alkylating agent, although toxicity pattern differs slightly from other alkylating agents.
Myelosuppression is dose limiting
MOA of platinum drugs? What is the original prototype?
They are covalent crosslinkers. Cisplatin is the original prototype.
What does cisplatin turn into inside of the cell?
Cisplatin turns into aquo form inside of cell.
Aquo form is highly reactive and a potent electrophile
What do aquo forms react rapidly with?
Aquo forms react rapidly with other nucleophiles, especially thiols
What type of cross links do platinum drugs form? What is the use of this?
Cross links are often intrastrand. Intra strand cis plat cross links impose severe geometrical constraints on DNA
What base pairs do aquo forms primarily act on?
Guanine N-7 and adenine N-7 in DNA
What are the geometric constraints on DNA platinum drugs impose
Introduce sharp bend in cross linked strand.
lesion not readily repaired by standard DNA repair enzymes
What is the major difference between platinum and alkylators?
The type of cross link it forms and side effect profile
Side effects of cis platin (dose limiting)
Dose limiting- nephrotoxicity
severe N/V
minimal bone marrow toxicity
peripheral neuropathy
drug resistance mechanism of cisplatin (2 main ones)
- Increased expression of glutathione-s-transferase (GST)
- increased intracellular concentration of non-protein thiols, especially glutathione
Why would increased expression of GST cause resistance to cisplatin
Free thiols have extremely high reactivity toward electrophilic intermediates
Thiols intercept the reactive intermediates of alkylating agents
Free thiol levels > 10-fold higher in alkylating agent-resistant cells
GST catalyzes the reaction of glutathione with alkylating agents (parent
drugs as well as reactive intermediates)
Why would increased concentration of non protein thiols cause resistance to cisplatin
Free thiols have extremely high reactivity towards electrophilic intermediates
Thiols intercept the reactive intermediates of alkylating agents
̈ Free thiol levels > 10-fold higher in alkylating agent-resistant cells
o block hemorrhagic cystitis, Mesna is coadministered with
which drug?
A. Methotrexate
B. Cyclophosphamide
C. Cisplatin
D. Mitomycin C
cyclophosphamide
Which of the following is NOT a crosslinker?
A. Cytarabine
B. Cyclophosphamide
C. Carboplatin
D. Chlorambucil
cytarabine
what do topoisomerases do?
topoisomerases provide a mechanism to reduce localized supercoiling and provide access to double stranded DNA by enzymes responsible for replication, transcription and repair.
What are the different kinds of topoisomerase inhibitors and Name their drugs (along with what stage they inhibit)
Topo I inhibitor- Irinotecan (targets S phase (DNA replication))
Topo II inhibitor- etoposide and bleomycin (Target G2 phase (sister chromatid separation))
Topo 2 intercalator- doxorubicin- non cell cycle specific
Topoisomerase I MOA
Topo I inhibitor MOA
Type I topoisomerase cuts one strand of double stranded DNA, relaxes remaining strand and reanneal.
Topo I inhibition provides a physical barrier to replication and transcription (acts as a road block)
Clinically relevant topoisomerase inhibitors bind to and form
a ternary drug-enzyme-DNA complex Inhibitor binding stabilizes Topo-DNA complex and blocks DNA re-
ligation
Cells in what phase are most sensitive to Topo I cleavage
Cells in S phase
Drug resistance of Topo I inhibitor
P-glycoprotein (PGP) overexpression
̈ Multidrug resistant protein (MRP) overexpression
̈ Glutathione S-transferase overexpression
What kind of drug are the camptothecins? Name the camptothecins.
Potent topo I inhbitors
topotecan and irinotecan
What is irinotecan broken down into?
SN-38
SN-38 is metabolized by
UGT1A1
What causes increased risk of toxicity for irinotecan in some people? What portion of population does this occur in?
10% of population has polymorphisms predicting low expression of UGT1A1 leading to increasein toxicity in irinotecan users
(remember irinotecan is broken down to SN 38. SN 38 is metabolized by UGT 1A1.)
Topo2 MOA
Topoisomerase II (Top2) relieves torsional strain AND
untangles DNA by catalyzing double-stranded DNA breaks
Many compounds inhibit Top2
Only ones that produce ________________ are chemotherapies
double strand DNA break
What type of drug is doxorubicin? toxicity?
It is a topo II inhibitor that is non cell cycle dependent
biggest toxicity is cardiotoxicity
severe local tissue damage if extravasated
Why is there cardiotoxicity with doxorubicin
doxorubicin is an intercalator that causes free radical damage. free radical damage causes cardiotoxicity. This is because the heart tissue has low levels of enzymes that neutralize free radicals.
(Cardiotoxicity of doxorubicin believed to be caused by iron-catalyzed free radical formation)
What is a drug that mediates toxicity to doxorubicin
dexrazoxane
MOA of how dexrazoxane mediates doxorubicin toxicity
MOA- enters cell and binds to iron, blocks iron-oxygen induced toxicity
Does dexrazoxane interfere with the anti tumor effect of doxorubicin?
No
What type of drug is etoposide? MOA? What cell cycle does it inhibit?
Etoposide is a Topo II inhibitor.
It inhibits religation of double stranded breaks induced by topo II, but does not intercalate
G2 block- cell cycle specific
What is resistance to Topo II inhibitors caused by?
Glutathione-S-transferase overexpression in doxorubicin only
PGP overexpression
MRP overexpression
increased DNA damage repair
Topo II downregulation or mutation
What type of drug is bleomycin? MOA? toxicity (dose limiting)? What cell cycle does it affect?
Bleomycin is a topo II inhibitor
It intercalates into DNA and generates free radicals. Radical intermediate leads to DNA single strand break and double strand break.
greatest effect is on G2 and M phase
toxicity- pulmonary toxicity is dose limiting effect
Why does bleomycin cause pulmonary and skin side effects
Bleomycin is inactivated by bleomycin aminohydrolase, which is in high concentration everywhere, but skin and lung
What is the role of microtubule during cell division
Microtubules are an essential part of mitotic spindle
It is responsible for moving chromosomal material into daughter cell during mitosis
What phase in cell cycle do microtubules act on?
M phase
Name microtubule inhibitor drugs
Vincristine and paclitaxel
Describe the requirements for spindle assemble checkpoint? Compare normal cells and cancerous cell
Kinetochores need to be attached to spindle microtubules. There needs to be kinetochore tension.
Cancer cells do not have checkpoints, if a normal cell has a good checkpoint, it will not start dividing until there is kinetochore tension. In a cancer cell, you are unable to reach checkpoint that leads to cell death or messed up cell division.
What are two major classes of microtubule inhibitors drug ?
Vinca alkaloids
taxanes
Difference in MOA between the two classes of microtubule inhibitor drugs? Why do they work?
Vinca alkaloids prevent microtubule assemble
taxanes prevent microtubule disassembly
Even though they have opposite effects, microtubules need dynamic instability. Microtubules need to elongate and shorten and these drugs prevent that
Name microtubule destabilizers
Vinca alkaloid
Erubulin
vinca alkaloid MOA, toxicity, resistance
Vinca alkaloids bind to tubulin. This binding leads to inhibition of microassembly (polymerization)
peripheral neuropathy is a toxic side effect
excellent substrate for PGP
name a vinca alkaloid
Vincristine
Vincristine toxicity (dose limiting)
Neurotoxicity is the dose limiting toxicity
extravasation causes SEVERE local inflammation
neurologic assessment prior to each dose
compare eribulin and vinca alkaloids in terms of MOA and toxicity
different MOA than vinca alkaloids. Eribulin MOA is it is a microtubule polymerization inhibitor that binds at microtubule ends and prevents elongation. Vinca alkaloids inhibit elongation and shortening at + end
Eribulin has a lower rate of neurotoxicity
What are the microtubule stabilizers?
Taxanes
Epothilones
taxanes bind to tubulin with two consequences, what are they
- promotion of microtubule assembly into stable (non-functional) bundles decreases free tubulin and prevents microtubule formation at spindle
- stabilization of existing microtubules blocks depolymerization
this leads to mitotic arrest
Taxane drug resistant mechanism
it is an excellent substrate for pGP. Drug rapidly pumped out of resistant cells. It is also cross resistant with other large molecule antitumor agents
Name a taxane drug. What is its toxicity (dose limiting)
Paclitaxel
it is linked to albumin to increase stability and circulation time
toxicity- myelosuppression is dose limiting
neurotoxicity is also common
Epothilones MOA, toxicity and name a drug
Toxicity- neurotoxicity (reversible)
Binds to tubulin and promotes tubulin polymerization and microtubule stabilization
ixabepilone
are epothilones cross resistant with taxanes? Are epothilones good PGP substrates
Epothilones are not cross resistant with taxanes. Poor pgp substrate
