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therapeutics 864 - exam 1 > alkylators & platinum > Flashcards

alkylators & platinum Flashcards

1
Q

Alkylators & intercalators inhibit what phase of cell cycle

A

All of them

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2
Q

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)

A

electrophilic; neutrophilic; alkyl

purine; DNA

Guanine N7

Cross

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3
Q

t/f alkylators are NOT cell-cycle phase specific

A

true

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4
Q

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

A

leukemia & lymphoma (myelosuppression)

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5
Q

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

They were the first chemotherapy in 1942.

Very reactive and excessively toxic

A

Nitrogen; liquid

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6
Q

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.

A

nitrogens; neutrophilicity; hydrogen bonds

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7
Q

Alkylating agents are potent…

A. Reducing agents

B. Electrophiles

C. Nucleophiles

D. Oxidizing agents

A

B. Electrophiles

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8
Q

match with correct definition:
intrastrand or interstrand

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

IntRAstrand linking between two bases on the same strand

intERstrand cross-linking of two separate strands

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9
Q

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

also _______ and _________ residues in proteins

A

alkylating

thiols & amines

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10
Q

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

A

glutathione

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11
Q

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

A

G1 & S; non cell cycle

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12
Q

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

A

bone marrow & gut mucosa

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13
Q

_________ 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)

A

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

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14
Q

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

A

mechlorethamine (mustargen, mustine, chlormethine)

> extremely reactive compound

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15
Q

what are 3 side effects for all alkylators?

A

myelosuppression
N/V
carcinogenic & teratogenic

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16
Q

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

A

teratogenic

17
Q

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

A
  1. decrease nucleophilicity of nitrogen by adding aryl groups (chlorambucil)
  2. prodrug strategy –> requires hydroxylation by hepatic cytochrome P450 (cyclophosphamide)
18
Q

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

A

chlorambucil & cyclophosphamide

19
Q

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?

A

cytochrome P450

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

aldehyde dehydrogenase

20
Q

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?

A

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

21
Q

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

A

hemorrhagic cystitis

22
Q

what is the most useful & commonly used alkylating agent?

A

cyclophosphamide

23
Q

Which of the following is a prodrug?

  1. Mechlorethamine
  2. Cyclophosphamide
  3. Mitomycin C
  4. Chlorambucil
A
  1. Cyclophosphamide
24
Q

what are the 2 unique sxs associated with cyclophosphamide

A

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

25
Q

mitomycin C is a ______-containing natural product

A

aziridine

26
Q

what is the dose-limiting side effect of mitomycin c

A

myelosuppression

27
Q

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

A

bifunctional adducts

28
Q

t/f platinum drugs are considered alkylating agents

A

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

29
Q

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

A

cisPLATin; cis

30
Q

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)

A

reversible

plasma; high

inside; low

aquo form; electrophile

nucleophiles

31
Q

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

A

Guanine N-7 and Adenine N-7

INTRAstrand –> crosslinks induce sharp bends & lesions are not readily repaired by standard DNA repair enzymes

32
Q

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

A

solid

S or G2

33
Q

what is a dose-limiting side effect of cisplatin?

what are some other unique sxs?

A

nephrotoxicity

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

34
Q

what is the most prescribed chemotherapy?

A

cisplatin

35
Q

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)

A

Increased

increased

glutathione

Glutathione

electrophilic

10 fold

glutathione S-transferase

II

isozyme

glutathione

36
Q

To block hemorrhagic cystitis, Mesna is coadministered with which drug?

A. Methotrexate

B. Cyclophosphamide

C. Cisplatin

D. Mitomycin C

A

B. Cyclophosphamide

37
Q

Which of the following is NOT a crosslinker?

A. Cytarabine

B. Cyclophosphamide

C. Carboplatin

D. Chlorambucil

A

A. Cytarabine

therapeutics 864 - exam 1 (10 decks)

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