Alkylating Agents and Platinum Compounds - Chemo

Question 1

what rescues a 5-FU overdose?
a) leucovorin
b) cytosine arabinoside
c) thymidine
d) methotrexate

Answer 1

thymidine

Question 2

what increases the efficacy of 5-FU?
a) leucovorin
b) cytosine arabinoside
c) thymidine
d) methotrexate

Answer 2

leucovorin

Question 3

which antimetabolite should not be given to pateints being treated for gout?
a) cytosine arabinoside
b) 6-mercaptopurine
c) cladribine
d) 5-FU

Answer 3

6-mercaptopurine

Question 4

which anti-metabolite dose not directly inhibit DNA/RNA synthesis?
a) 5-FU
b) cytosine arabinoside
c) nelarabine
d) methotrexate

Answer 4

methotrexate

Question 5

Alkylating Agents

• drugs that generate reactive ___ (electron deficient) intermediates and react with nucleophilic (electron rich) groups on DNA and proteins
• result in attachment of ___ (hydrocarbon) group to DNA and protein
• MOA: alkylation of ___ bases in DNA - guanine N7
• ___ inhibit DNA replication as well as transcription (NOT cell-cycle ___ - mess up every phase)
• ___ of cross-links in cancer cells is not efficient
• attempted replication of modified DNA can result in ___
• most effective anti-cancer drugs are bifunctional alkylating agents that produce ___ and ___ strand linkages

Answer 5

• electrophilic
• alkyl
• cross-links
• specific
• repair
• apoptosis
• intra, inter

Question 6

Alkylating agents history - WWI

sulfur mustard gas
- soldiers were observed to have ___ suppression and ___ shrinkage
- first leukemia and lymphoma treatment in 1940s

Answer 6

• bone marrow, lymph node

Question 7

nitrogen mustards are similar but are ___ , not ___
- very reactive and excessively ___

Answer 7

liquid, gas
- toxic

Question 8

purine bases in DNA

Answer 8

all of the ring nitrogens have some reactivity, as well as the exocyclic oxygens. the nucleophilicity is controlled by steric, electronic, and hydrogen bonding effects

Question 9

alkylating agents are potent
a) reducing agents
b) electrophiles
c) nucleophiles
d) oxidizing agents

Answer 9

electrophiles

Question 10

Effects of DNA Alkylation

alkylating agents react with many nucelophiles other than DNA bases
- thiols and amines especially reactive
- cysteine and lysine residues in proteins
- protein adducts occasionally trigger an ___ response
- ____ in cells can react with alkylating agents and “ quench “ their activity.

toxicity to cancer cells results from DNA ___ and DNA ___
- DNA-protein cross-links also inhibit DNA function

cells are more susceptible in late
___ and ___ phases of the cell cycle by alkylaying agents are considered ___ ___

Answer 10

• allergic
• glutathione
• alkylation, crosslinking
• G1, S, non-cycle specific

Question 11

cell cycle checkpoints and common chemotherapies

DNA damaging agents (Non-cycle specific)
- alkylators/platinum
- (5)

Answer 11

• Chlorambucil
• Cyclophosphamide
• Mitomycin C
• Cisplatin
• Radium-223

Question 12

side effects of alkylation

some normal cell populations are rapidly ___ and therefore are sensitive to effects of DNA alkylation and cross-linking (bone marrow, gut mucosa)

monoadducts are mutagenic and carcinogenic
- measurable incidende of ___ ___ in long term survivors
- most arise in the ___ ___ (mostly leukemias)

Answer 12

• proliferating
• 2nd malignancies
• bone marrow

Question 13

T or F: crosslinkers cause only one type on DNA damage

Answer 13

FALSE

Question 14

Mechlorethamine (Mustargen, Mustine, Chlormethine)

first used clinically in the 1940s - not commonly used anymore

extremely reactive compound (t1/2 ~ 1min)
- rapidly alkylates all ___ - modifies DNA, RNA, and protein
- antitumor activity correlates with DNA ___

SE of all alkylators
- ___ suppression
- N/V
- ____ genic and ___ genic

Answer 14

• nucleophiles
• cross-links
• myelosuppression
• carcinogenic, teratogenic

Question 15

Mechlorethamine Derivatives

Two strategies have been employed to reduce reactivity and increase selectivity of nitrogen mustards
1) decrease nucleophilicity of nitrogen by adding ___ groups
- examples: Chlorambucil, bendamustine, melphalan

Answer 15

• aryl

Question 16

T or F: aryl groups increased nucleophilicity

Answer 16

FALSE; reduce nucleophilicity

Question 17

“wait, why dose adding an aryl make it less reactive? I thought they were electrophiles?”

the aziridinium intermediate is the ___ group
- primary amines (better ___ ) form aziridinium intermediates much faster; therefore, they are more ___

Answer 17

• electrophilic
• nucleophiles
• reactive

Question 18

Mechlorethamine Derivatives

Two strategies have been employed to reduce reactivity and increase selectivity of nitrogen mustards
2) prodrug strategy - cyclophosphamide

chemically stable prodrug - requires ___ by hepatic CYP450
- phosphoramide mustard (PM) is the metabolite that cross-links
- hydroxylated metabolite must be converted to PM in the tumor cells
- PM is highly ___ and does not readily diffuse into cells
- PM has a ___ t1/2

metabolite inactivated by aldehyde dehydrogenase
- elevated aldehyde dehydrogenase in some bone marrow progenitor cells accounts for ___ bone marrow toxicity

Answer 18

• hydroxylation
• polar
• short
• reduced

Question 19

Cyclophosphamide

most useful and commonly used alkylating agent

SE modest compared to most agents
- mild bone marrow toxicity - sparing to marrow stem cells and platelets because of high ___ levels in these cell types
- hemorrhagic cyctitis - ___ is toxic to bladder mucosa

also in this class: ifosamide has longer t1/2 than cyclophosphamide but also has ___ CNS toxicity

Answer 19

• ADH
• acrolein
• increased

Question 20

Mesna

cyclophosphamide is toxic to the bladder
- ___ accumulates in urine and damages bladder mucosa

mesna containing a charged anionic sulfonate group so it does not ___ cells
- anion transporters in proximal tubule excrete via kidney
- mesna accumulates in the ___ (and therefore in the bladder
- the free thiol on mesna reacts with and inactivates ___ metabolites in urine
- administered with cyclophosphamide to block hemorrhagic cystitis

Answer 20

• acrolein
• penetrate
• urine
• acrolein

Question 21

Mitomycin C (Mutamycin)

• aziridine-containing natural product
• functions as an alkylating agent, although ___ pattern differs slightly from other alkylating agents
• ___ is dose limiting
• form ___ adducts (crosslinks)

Answer 21

• toxicity
• myelosuppression
• bifunctional

Question 22

which of the following is a prodrug?
a) mechlorethamine
b) cyclophosphamide
c) mitomycin C
d) chlorambucil

Answer 22

cyclophosphamide

Question 23

Platinum Drugs

• ___ crosslinkers, but not ___ agents
• cisplatin is the original prototype square planar complex with leaving groups having ___ geometry

Answer 23

• covalent, alkylating
• cis

Question 24

Platinum drugs

cisplatin undergoes ___ hydrolysis in aqueous solution
- equilibrium favors cisplatin in ___ (where there is a ___ chloride concentration)
- equilibrium favors aquo form ___ cell ( ___ chloride concentration)
- aquo form is highly ___ and a potent electrophile. Reacts rapidly with other nucleophiles, especially thiols

also in this class:
- carboplatin
- oxaliplatin

Answer 24

• reversible
• plasma, high
• inside, low
• reactive

Question 25

# platinum crosslink geometry - aquo form reacts primarily at ___ N-7 and ___ N-7 in DNA - because of bond lengths and angles, cross-links are often ___ strand - ___ strand ___ - Pt cross link imposes severe geometrical constraints on DNA - introduces sharp bend in cross-linked strand - lesion NOT readily repaired by standard DNA repair ___

Answer 25

- guanine, adenine - intrastrand - intrastrand, cis - enzymes

Question 26

# Cisplatin highly effective agent for many solid tumors - drug requires non- ___ conversion to the active aquo form - aquo form produces primarily ___ strand cross-links - crosslinks, form more ___ than other alkylating agents - some tumor cells more sensitive in ___ than in ___ phase SE profile very different from other alkylating agents: - dose-limiting ___ - severe N/V - ___ bone marrow toxicity (good in combo with other drugs) - peripheral ___ - related to cumulative dose - ototoxicity

Answer 26

- enzymatic - intrastrand - slowly - G1, S - nephrotoxicity - minimal - neuropathy

Question 27

# drug resistance - general mechanisms ___ expression of DNA repair enzymes **increased intracellular concentration of non-protein thiols, especially, ___** - glutathione is a ___ -containing tripeptide - free thiol have extremely ___ reactivity toward electrophilic intermediates - thiols intercept the reactive intermediates of alkylating agents - free thiol levels are more than 10x ___ in alkylating agent resistant cells **___ expression of cellular glutathioe S-transferase (GST)** - GST's are a family of phase II metabolic enzymes - GST catalyzes the reaction of ___ with ___ agents (parent drugs as well as ractive intermediates)

Answer 27

- increased - glutathione - cysteine - high - higher - increased - glutathione, alkylating