alkylators & platinum

Question 1

Alkylators & intercalators inhibit what phase of cell cycle

Answer 1

All of them

Question 2

Alkylating agents are drugs that generate reactive __neutrophilic/electrophilic__ intermediates that react with __electrophilic/nucleophilic__ groups on DNA and proteins.

Result in the attachment of an _____(hydrocarbon) group to DNA and protein.

Major mechanism of action involves alkylation of __purine/pyrimidine__ bases in __DNA/RNA__

> _______ is the most common site of alkylation

Most effective anti-cancer drugs are bifunctional alkylating agents (two alkylating groups) that produce DNA intra- and interstrand linkages

_______-links inhibit DNA replication, as well as transcription

Repair of cross-links in cancer cells is not efficient

Attempted replication of modified DNA can result in cell death (apoptosis)

Answer 2

electrophilic; neutrophilic; alkyl

purine; DNA

Guanine N7

Cross

Question 3

t/f alkylators are NOT cell-cycle phase specific

Answer 3

true

Question 4

doctors first used mustards to tx ______ and ______ in the 1940s

Answer 4

leukemia & lymphoma (myelosuppression)

Question 5

_______ mustards (Chlormethamine, Mechlorethamine, Mustine R=CH3):
Are similar, but are _____, not gas.

They were the first chemotherapy in 1942.

Very reactive and excessively toxic

Answer 5

Nitrogen; liquid

Question 6

All of the ring __nitrogens/carbons______have some reactivity, as well as the exocyclic oxygens.

The __electrophilicity/nucleophilicity__ is controlled by steric, electronic and ________bonding effects.

Answer 6

nitrogens; neutrophilicity; hydrogen bonds

Question 7

Alkylating agents are potent…

A. Reducing agents

B. Electrophiles

C. Nucleophiles

D. Oxidizing agents

Answer 7

B. Electrophiles

Question 8

match with correct definition:
intrastrand or interstrand

1. linking between two bases on the same strand
2. cross-linking of two separate strands

Answer 8

IntRAstrand linking between two bases on the same strand

intERstrand cross-linking of two separate strands

Question 9

_________ agents react with many nucleophiles other than DNA bases. Thiols especially reactive, amines also reactive

also _______ and _________ residues in proteins

Answer 9

alkylating

thiols & amines

Question 10

___________ in cells can react with alkylating agents and ”quench” their activity.

Answer 10

glutathione

Question 11

cells are more susceptible in late ___ and ___ phases of the cell cycle but alkylating agents are considered _______ specific

Answer 11

G1 & S; non cell cycle

Question 12

what normal cell populations are more sensitive to effects of DNA alkylation & cross-linking because they are naturally rapidly proliferation?

Answer 12

bone marrow & gut mucosa

Question 13

_________ are a side effect of alkylation and are mutagenic and carcinogenic

> Measurable incidence of second malignancies in long-term survivors following chemotherapy with alkylating agents

Most __first/second__ malignancies arise in the bone marrow (leukemias)

Answer 13

Monoadducts
second –> myelosuppression (hair loss, N/V)

Question 14

what drug was an important prototype that resulted in the development of field of chemotherapy, but is not used commonly anymore?

Answer 14

mechlorethamine (mustargen, mustine, chlormethine)

> extremely reactive compound

Question 15

what are 3 side effects for all alkylators?

Answer 15

myelosuppression
N/V
carcinogenic & teratogenic

Question 16

why should someone who is pregnant that is wanting to preserve the pregnancy not use alkylators

Answer 16

teratogenic

Question 17

For mechlorethamine (mustards) derivatives:

what 2 strategies have been employed to reduce reactivity & increase selectivity of nitrogen mustards? give a drug example of each strategy

Answer 17

1. decrease nucleophilicity of nitrogen by adding aryl groups (chlorambucil)
2. prodrug strategy –> requires hydroxylation by hepatic cytochrome P450 (cyclophosphamide)

Question 18

what are the 2 main mechlorethamine derivative that we need to know?

Answer 18

chlorambucil & cyclophosphamide

Question 19

cyclophosphamide is a stable prodrug (mechlorethamine) that requires hydroxylation by hepatic _________.

what is the metabolite that cross-links DNA?

what metabolite inactivates the metabolite that cross-links?

Answer 19

cytochrome P450

phosphoramide mustard (hydroxylated metabolite must be converted to PM in tumor cell)

aldehyde dehydrogenase

Question 20

what is the byproduct that is produced by cyclophosphamide?

what part of the body is this toxic to?

What needs to be administered with cyclophosphamide to prevent accumulation?

Answer 20

acrolein

bladder –> damages bladder mucosa

Mesna –> contained anionic sulfonate group does not penetrate cells & accumulates in urine. the free thiol on mesna reacts with acrolein and inactivates it

Question 21

if mesna is not administered with cyclophosphamide what can tx lead to?

Answer 21

hemorrhagic cystitis

Question 22

what is the most useful & commonly used alkylating agent?

Answer 22

cyclophosphamide

Question 23

Which of the following is a prodrug?

1. Mechlorethamine
2. Cyclophosphamide
3. Mitomycin C
4. Chlorambucil

Answer 23

2. Cyclophosphamide

Question 24

what are the 2 unique sxs associated with cyclophosphamide

Answer 24

-mild bone marrox toxicity (high ADH levels in these cells)
-hemorrhagic cystitis (byproduct, acrolein is toxic to bladder mucosa)

Question 25

mitomycin C is a ______-containing natural product

Answer 25

aziridine

Question 26

what is the dose-limiting side effect of mitomycin c

Answer 26

myelosuppression

Question 27

what kind of crosslinks does mitomycin C form to disrupt DNA?

Answer 27

bifunctional adducts

Question 28

t/f platinum drugs are considered alkylating agents

Answer 28

FALSE; covalent crosslinkers --> they do not contain alkyl groups

Question 29

___drug_______ is the orig. prototype square planar complex with leaving groups having __cis/trans___

Answer 29

cisPLATin; cis

Question 30

Cisplatin undergoes __irreversible/reversible___ hydrolysis in aqueous solution Equilibrium favors Cisplatin in ______ (where there is a __high/low__ chloride concentration) Equilibrium favors aquo form __inside/outside___cell (__high/low___ chloride concentration) __cisplatin/aquo form___ is highly reactive and a potent __neutrophile/electrophile___ therefore, it reacts rapidly with other __neutrophiles/electrophiles__ especially thiols (glutathione)

Answer 30

reversible plasma; high inside; low aquo form; electrophile nucleophiles

Question 31

The aquo form of cisplatin reacts primarily with _________ and _________ in DNA. The reaction results in cross-links that are often __interstrand/intrastrand__

Answer 31

Guanine N-7 and Adenine N-7 INTRAstrand --> crosslinks induce sharp bends & lesions are not readily repaired by standard DNA repair enzymes

Question 32

cisplatin is highly effective for many ______ tumors. some tumor cells are more senstive in G1 than S phase, so cisplatin is often combined w drugs that target ___ or ___ phase

Answer 32

solid S or G2

Question 33

what is a dose-limiting side effect of cisplatin? what are some other unique sxs?

Answer 33

nephrotoxicity -severe N/V -minimal bone marrow toxcity (myelosuppresion) -peripheral neuropathy -ototoxicity

Question 34

what is the most prescribed chemotherapy?

Answer 34

cisplatin

Question 35

drug resistance of alkylating/platinum agents: ___increased/decreased___ expression of DNA repair enzymes ___increased/decreased___ intracellular concentration of non-protein thiols, especially __________ >________ is a cysteine-containing tripeptide (gamma-Glu-Cys-Gly) >Free thiols have extremely high reactivity toward __neutrophilic/electrophilic___ intermediates >Thiols intercept the reactive intermediates of alkylating agents >Free thiol levels > _#__-fold higher in alkylating agent-resistant cells Increased expression of cellular _________________ (GST) >GST’s are a family of Phase _____ metabolic enzymes – P1-1 is key ________ >GST catalyzes the reaction of ___________ with alkylating agents (parent drugs as well as reactive intermediates)

Answer 35

Increased increased glutathione Glutathione electrophilic 10 fold glutathione S-transferase II isozyme glutathione

Question 36

To block hemorrhagic cystitis, Mesna is coadministered with which drug? A. Methotrexate B. Cyclophosphamide C. Cisplatin D. Mitomycin C

Answer 36

B. Cyclophosphamide

Question 37

Which of the following is NOT a crosslinker? A. Cytarabine B. Cyclophosphamide C. Carboplatin D. Chlorambucil

Answer 37

A. Cytarabine