Antineoplastic agents- Friel

drug A

Which structure is an aromatic nitrogen mustard?

Which atom is the most nucleophilic on DNA?

N-7 guanine

What determines the speed of activation of nitrogen mustards?

R-group on molecule, alkyl groups undergo an intranucleophilic attack faster than aromatic rings

drug b

Which new drug in clinical trials will undergo aziridine ring formation the fastest?

Why does mechlorethamine require strict refrigeration?

It gets inactivated at room temperature

Why are nitrogen mustards manufactured in acid?

To make the nitrogen predominately protonated, which will slow activation via an intranucleophilic attack

What other molecule can nitrogen mustards attack, besides N-7 guanine?

thiol groups

During the administration of mechlorethamine, a patient experiences extravasatation. After cross clamping the IV and aspirating the line, what are the most appropriate next steps?

a. Apply local heat and topical DMSO

b. Apply local heat and subQ hyaluronidase

c. Apply local cooling and IV dexrazoxane

d. Apply local cooling and subQ sodium thiosulfate

d. Apply local cooling and subQ sodium thiosulfate

Which are more active in alkylating agents, quaternary or tertiary nitrogens?

Quaternary nitrogens are more active because the positive charges pull electrons making the carbon very electrophilic

Which amino acid is melphalan an analog of?

L-phenylalanine

Which nitrogen mustards can be given orally

aromatic and its activation is slow enough not to cause damage to GI tract; also, cyclophosphamide because it is a prodrug

How is cyclophosphamide activated?

It's hydroxylated in the liver to form a carbinolamine compound

How is chloroacetaldehyde formed?

It's formed by oxidation of the alpha carbon and is nephro/neurotoxic

acrolien

what is this compound

How is acrolein formed?

Spontaneous cleavage of carbinolamine compound and decomposition via hydrolysis

What is the antidote for hemorrhagic cystitis (bladder toxicity) caused by cyclophosphamide and ifosfamide?

MESNA

drug b

MESNA could be administered with which drug to decrease bladder toxicity?

How is ifosfamide activated?

It undergoes hydroxylation at C-4 to form a cytotoxic metabolite

Why does ifosfamide produce more acrolein than cyclophosphamide?

It is a tertiary amine, less potent and requires a higher dose; more ifosfamide = more acrolein

Why does ifosfamide produce more chloroacetaldehyde than cyclophosphamide?

It has less steric hinderance around the alpha carbon, so it's easier for CYP enzymes to hydroxylate

How is thiotepa "activated"?

It's activated in an acidic pH because the nitrogen has to be protonated

What is cisplatin mixed with to prevent early activation?

It's mixed with NaCl because the chloride ions on NaCl will prevent the chloride ions on cisplatin molecule from dissociating and becoming active

Does cisplatin cause interstrand cross-links?

Doesn't occur because the molecule is too small to reach both strands

What is the active form of oxaliplatin?

oxaliplatin diaquo form, cisplatin is active in mono/diaqua forms

structure A

Nedaplatin is used in Japan as an oncology agent. Based on your knowledge of this drug class, which structure shows mono-alkylated DNA by this agent?

structure b

Which structure shows diaquo-alkylated DNA by platinum agents?

Which alkylating agents decompose to form isocyanate?

nitrosoureas

Which nitrosourea is really unstable and can break down on the shelf in high temperature?

carmustine

Which nitrosourea is given in an oral formulation?

lomustine

What metabolite is responsible for carbamoylation of proteins?

Isocyanate

drug A

Which drug can generate isocyanate upon decomposition inside the tumor cell?

What enzymes convert 5-FU to 5-FdUMP

Ribosyl transferase (adds sugar) and uridine kinase (adds phosphate)

Why does 5-FdUMP have a higher affinity for thymidylate synthase?

The added fluorine (EWG) makes it a stronger Michael acceptor than dUMP, so it attacked more readily by SH-Cys of TS

What enzyme inactivates bleomycin?

Bleomycin hydrase, which is not found in the lung or skin

What is the color of bleomycin, naturally?

blue

How does bleomycin generate free radicals?

Binds iron, gets oxidized to Fe3+, generates ROS next to DNA, and produces ssDNA breaks

Which part of the dactinomycin molecule generates free radicals?

quinone

What is the color of dactinomycin?

red

What are the storage conditions for dactinomycin?

protect from light

Which anthracycline can cross the blood-brain barrier?

Idarubicin

drug a, c, e

Select all that apply:Which drug below generates free radicals?

B

Which part of the structure of tyrosine kinase inhibitors of EGFR covalently binds to cysteine 797 of the EGFR via a Michael addition?

Can Osimertinib covalently inhibit EGFR?

yes

drug d

Which structure contains a tertiary aziridine ring?