DNA Cross-Linking Agents I Flashcards
True or False - The N of the purine guanine (N=CH) is highly reactive and can be easily alkylated?
True
7-methylguanosine is used in conjunction with a __________ group to mark mRNA starting point for nucleotide methylation?
Triphosphate group
True or False - uncontrolled methylation can cause mutations?
True
Which of the following statements is false?
A. alkylation can be used therapeutically
B. nucleophilic attack of unstable aziridine ring by electron donor activates nitrogen mustards
C. One Nitrogen mustard compound can bind two DNA bases
D. Nitrogen mustards are covalently linked to a single DNA strand
E. alkylating agents’ reactive electrophilic structures allow them to cross link e- rich DNA bases
(D) is FALSE
Nitrogen mustards are covalently linked to TWO DIFFERENT DNA strands
Alkylation can be used therapeutically to inflict damage to fast-dividing cells (tumors)
Is DNA polymerase able to repair a strand of DNA cross linked with nitrogen mustard?
A. Yes
B. No
C. Need more info
(B) - No
What is the result of water reacting with an active nitrogen mustard?
Water can deactivate nitrogen mustard by kicking off the Cl- ions turning it into an INACTIVE dehalogenated DIOL
Which of the following nitrogen mustards is MOST reactive?
A. Mechlorethamine hydrochloride (Mustargen ®) B. Cyclophosphamide (Cytoxan ®) C. Thiotepa (Thioplex ®) D. Melphalan (Alkeran ®) E. Chlorambucil (Leukeran ®)
(A) Mechlorethamine hydrochloride (Mustargen ®) is most reactive b/c the lone pair of e- are on the nitrogen atom (compared to the other nitrogen mustards listed that have the lone pair of e- conjugated with an aromatic or double bond)
Which of the following statements about Mechlorethamine hydrochloride is FALSE?
A. very lipophilic drug B. administered as an injection C. severe vesicant D. can cause secondary cancers E. less reactive than other nitrogen mustards and thus lower toxicity
(E) the use of Mechlorethamine hydrochloride (Mustargen ®) is limited by its extremely high reactivity and EXCESSIVE toxicity. It is non-specific alkylator of cellular nucleophiles
True or False - Mechlorethamine hydrochloride is orally bioavailable?
False - not orally bioavailable, must be INJECTED
Which of the following pairs is matched incorrectly?
A. Thiotepa - Tx of testicular cancer, solid tumors, and hematologic cancers
B. Mechlorethamine hydrochloride - Tx of blood cancers (Hodgkin’s disease, leukemias)
C. Estramustine Phosphate Sodium - palliative Tx of progressive prostate cancer
D. Chlorambucil - palliative Tx of leukemias, lymphomas, Hodgkin’s disease
E. Cyclophosphamide - Used in combo for Tx of leukemias, malignant lymphomas, myelomas, ovarian and breast cancer
(A) Thiotepa is used to Tx OVARIAN and BREAST CANCERS
IPHOSPHAMIDE is used to Tx testicular cancer, solid tumors, and hematologic cancers
Which of the following is NOT a prodrug?
A. Thiotepa B. Iphosphamide C. Mechlorethamine D. Estramustine Phosphate Sodium E. Both A and C
(E) both A and C
Thiotepa (Thioplex) and Mechlorethamine (Mustargen) are NOT a prodrugs
All of the following can induce secondary leukemia except?
A. Melphalan B. Chlorambucil C. Mechlorethamine D. Thiotepa E. All of the above
(D) Thiotepa DOES NOT induce secondary leukemia.
Thiotepa (Thioplex) is very lipophilic so more CNS SE are seen (dizzy, HA, blurred vision) AND severe bone marrow suppression so patient at high risk for infection and hemorrhage
Which (2) nitrogen mustards produce two different nephrotoxic metabolites chloroacetaldehyde and acrolein? Which nitrogen mustard has significantly higher nephrotoxicity and bladder toxicity?
- Cyclophosphamide (Ctyoxan)
- Iphosphamide
Iphosphamide has significantly higher nephrotoxicity and bladder toxicity because 45% of prodrug is metabolized to chloroacetaldehyde compared to only 10% with cyclophosphamide.
Name the only aliphatic nitrogen mustard on the U.S. market?
Mechlorethamine hydrochloride (Mustargen)
Which of the following nitrogen mustards is NOT orally available?
A. Melphalan B. Chlorambucil C. Estramustine D. Mechlorethamine E. None of the above
(D) Mechlorethamine is the only one that is NOT orally available. It is given as an injection
Which nitrogen mustard used in the palliative Tx of progressive prostate cancer is metabolized to estradiol by hydrolysis?
Estramustine Phosphate Sodium (Emcyt)
True or False - Estramustine is used to treat estrogen-dependent tumors (i.e. breast cancer)?
False - Estramustine is NOT used to treat estrogen-dependent tumors. It is only used in the palliative Tx of progressive prostate cancer
This weak alkylating nitrogen mustard’s primary MOA of antineoplastic action is inhibition of cellular mitosis?
Estramustine (Emcyt)
Compared to Mechlorethamine, Melphalan has decreased reactivity mainly from?
A. orally activity B. mutagenic properties C. derived from L-Phe D. N-Ph conjugation E. none of the above
(D) Melphalan has decreased reactivity mainly from N-Ph conjugation (aka conjugation with phenyl ring)
Which of the following metabolisms are correctly matched?
A. Chlorambucil - B-oxidation B. Estramustine - hydrolysis C. Cyclophosphamide - CYP D. Thiotepa - oxidative desulfuration E. All of the above are correct
(E) all of the above are correct
What drug can be given to patients taking Cyclophosphamide to minimize bladder toxicity?
Mesna (Mesnex)
True or False - irrigation with diuretics is one way to minimize bladder toxicity in patients taking Cyclophosphamide?
True
Mesna (Mesnex) can also be given to minimize bladder toxicity
Name the active metabolite of Cyclophosphamide and Iphosphamide that is a highly reactive electrophilic species that can cause extensive damage to kidneys and bladder and potentially fatal acute hemorrhagic cystitis?
Acrolein
Increased BP, induced blood clots, and MI SE’s may be seen with what nitrogen mustard drug?
Estramustine (Emcyt) - due to conversion of estradiol. Estradiol can cause all these SE’s
