L alkylating and platinum

Question 1

alkylating agents are drugs that generate reactive ________ intermediates that react with ________ groups on DNA and proteins

Answer 1

electrophilic
nucleophilic

Question 2

the major MOA involves alkylation of ______ bases in DNA

Answer 2

purine

Question 3

what is the most common site of alkylation (answer has a nucelotide and something random)

Answer 3

guanine n7 (i later figured out that it is the nitrogen on the 7 position, im dumb)

Question 4

most effective anti-cancer drugs are ________ alkylating agents that produce DNA intra- and inter-strand linkages (whatever tf this means)

Answer 4

bifunctional, guess that makes sense with 2 things there huh

Question 5

Cross-links (caused by the alkylating groups that produce intra and inter strand dna linkages) inhibit what and what?

Answer 5

DNA replication
DNA transcription

Question 6

T or F:
alkylating agents are cell-phase specifc

Answer 6

false, they are not

Question 7

what common condiment is also a type of gas that can alkylate?

Answer 7

mustard lmao

Question 8

Alkylating agents are potent…

A. Reducing agents

B. Electrophiles

C. Nucleophiles

D. Oxidizing agents

Answer 8

B

Question 9

linking between two bases on the same strand
A. inTRAstrand
B. inTERstrand

Answer 9

A. inTRastrand

Question 10

cross-linking of two separate strands
A. inTRAstand
B. inTERstrand

Answer 10

B. inTERstrand

Question 11

what other nucleophilic-things can alkylating agents react with that aren’t DNA bases?

Answer 11

Thiols * (main one i think bc of sulfur)
amines
cysteine and lysine residues
glutathione

Question 12

T or F:
Toxicity to cancer cells results from DNA alkylation and DNA cross-linking

Answer 12

True

Question 13

T or F:
DNA-protein cross links also inhibit DNA function

Answer 13

true

Question 14

Cells are more susceptible to alkylating agents in what 2 phases of the cell cycle?

Answer 14

G1 and S

Question 15

what are the two locations in body that are most sensitive to DNA alkylation and cross-linking (important for side effects)?

Answer 15

bone marrow
gut mucosa

Question 16

T or F:
Mono-adducts are mutagenic but not carcinogenic

Answer 16

False, it is both mutagenic and carcinogenic

Question 17

There are a measurable incidence of 2nd malignancies in long-term survivors following chemo w/ alkylating agents, where do these malignancies arise?

Answer 17

bone marrow as leukemias

Question 18

3 side effects for all alkylators *

Answer 18

myelosuppression
N/V
carcinogenic and teratogenic

Question 19

Chlorambucil is a __________ derivative that decreases __________ of nitrogen by adding aryl groups

Answer 19

mechlorethamine
nucleophilicity

Question 20

what are the 2 strategies to reduce reactivity and increase the selectivity of nitrogen mustards (mainly just making mechlorethamine better)?

Answer 20

• decrease nucleophilicity of nitrogen by adding aryl groups
• prodrug strategy with cyclophosphamide that helps the mustard compounds get into cells

Question 21

what is another way of saying you added an aryl group

Answer 21

you added an aromatic ring

Question 22

Cyclophosphamide is a chemically stable ______

Answer 22

prodrug

Question 23

since cyclophosphamide is a prodrug, what does it require to be activated?

Answer 23

hydroxylation by CP450

Question 24

Phosphoramide mustard (PM) is the metabolite that _________ DNA
A. Creates an interstrand linkage with
B. Creates an intrastrand linkage with
C. Cross-links

Answer 24

C

Question 25

the hydroxylated metabolite from cyclophosphamide must be converted to PM, where does this happen?

Answer 25

in the tumor cell think that its a prodrug and has to have help getting into the cancer cells

Question 26

quick! you see the word "acrolein" on the exam, what do you start thinking about instantly because you studied hard?

Answer 26

Cyclophosphamide and aldehyde dehydrogenase

Question 27

what is an enzyme that can deactivate the metabolite derived from cyclophosphamide?

Answer 27

aldehyde dehydrogenase

Question 28

T or F: Aldehyde dehydrogenase inactivating the cyclophosphamide metabolites is bad

Answer 28

false, its actually good because we have higher levels of aldehyde dehydrogenase in our bone marrow and that means you reduce the activity there which leads to a reduction in myelosuppression (wordy af im sorry)

Question 29

Most commonly used and useful alkylating agent

Answer 29

cyclophosphamide

Question 30

2 side effects from cyclophosphamide slide**

Answer 30

-mild bone marrow toxicity -hemorrhagic cystitis (from acrolein metabolite)

Question 31

what is the drug in the same class as cyclophosphamide that has a longer half life with increased CNS toxicity?

Answer 31

Ifosfamide

Question 32

Cyclophosphamide is toxic to the _____ (organ). Why?

Answer 32

bladder, acrolein accumulates in urine and damages bladder mucosa

Question 33

T or F: Mesna penetrates cells

Answer 33

false, it cant because it has a charged sulfonate group

Question 34

Mesna accumulates in _______**

Answer 34

urine

Question 35

The free thiol on mesna reacts with and inactivates _____ metabolites in urine

Answer 35

acrolein

Question 36

Why is mesna administered with cyclophosphamide? **

Answer 36

To block hemorrhagic cystitis

Question 37

Mitomycin C functions as what?

Answer 37

an alkylating agent

Question 38

mitomycin C has a different toxicity pattern than other alkylating agents, what is the main difference with it? (not the reason behind the difference)

Answer 38

myelosuppression is dose-limiting

Question 39

Platinum drugs are _____ crosslinkers, but not ________ ________

Answer 39

covalent alkylating agents

Question 40

what drug is the OG prototype of platinum drugs

Answer 40

cisplatin (goated)

Question 41

cisplatin is a square planar complex with leaving groups having ____ geometry

Answer 41

cis, no fuckin way.

Question 42

T or F: Cisplatin undergoes irreversible hydrolysis in aqueous solution

Answer 42

false, it is reversible

Question 43

T or F: Equilibrium favors cisplatin in plasma

Answer 43

True, it's in the name bro come on

Question 44

Equilibrium favors aquo from (inside/outside) cell

Answer 44

inside

Question 45

aquo form is highly reactive and a potent _________

Answer 45

electrophile

Question 46

Cisplatin is given with what element as its leaving groups/

Answer 46

chlorine

Question 47

What replaces the Cl- leaving groups on cisplatin once it is in the cell?

Answer 47

water (h2o)

Question 48

Platinum crosslink geometry: Because of bond lengths and angles, cross-links are often ___________*

Answer 48

intrastrand

Question 49

T or F: Aldehyde dehydrogenase converts cisplatin to the active aquo form

Answer 49

False, it is a non-enzymatic conversion

Question 50

Cisplatin is a highly effective agent for many ____ tumors

Answer 50

solid

Question 51

Cross-links formed with cisplatin are generally (faster/slower) than for other alkylating agents

Answer 51

slower

Question 52

Cisplatin: Some tumor cells are more sensitive in __ phase than S phase

Answer 52

G1

Question 53

2 highlighted side effects on cisplatin slide (notably very different than other agents)

Answer 53

- dose limiting nephrotoxicity - minimal bone marrow toxicity

Question 54

Drug resistance - general mechanisms: Increased expression of DNA ______ enzymes

Answer 54

repair

Question 55

Drug resistance - general mechanisms: Increased intracellular concentration of non-protein thiols especially ______ **

Answer 55

glutathione

Question 56

Free thiols have extremely (low/high) reactivity toward electrophilic intermediates *

Answer 56

high

Question 57

Drug resistance - general mechanisms: increased expression of cellular _________________ *

Answer 57

glutathione S-transferase (GST)

Question 58

glutathione s-transferase (GST) catalyzes the reaction of ________ with __________ __________

Answer 58

glutathione alkylating agents