Alkylating Agents and Platinums

Question 1

Alkylating agents are cytotoxic and mutagenic, but they are not carcinogenic. True or false?

Answer 1

False. They are carcinogenic = they can cause other cancers

Question 2

Alkylating agents are cell-cycle specific. True or False?

Answer 2

False. They do not rely on cells being in a certain phase, and work on all phases of the cell cycle.

Question 3

What are 2 common toxicities related to alkylating agents due to bone marrow damage?
A) Hand Foot Syndrome
B) Hematopoietic suppression
C) Immunosuppression
D) N/V/D

Answer 3

B & C

Question 4

Alkylating agents covalently bind to alkyl groups to important cellular molecules and damage DNA. True or False?

Answer 4

True

Question 5

Alkylation includes which 2 mechanisms?
A) Methylation: addition of a methyl group causing problems with base pairing
B) Intercalation: incorporating itself into the DNA to cause cell death
C) Cross linking: formation of cross-bridges between bases either inter- or intra-strand binding
D) Microtubule Inhibition: Prevent the function of microtubules for DNA replication

Answer 5

A & C

Question 6

The following are subgroups of Alkylating agents EXCEPT: 
A) Nitrogen mustard gas derivatives
B) Nitroureas 
C) Triazenes
D) Alkylsulfonate
E) Cytidine analogs

Answer 6

E, that is a class of antimetabolites

Question 7

Cyclophosphamide, ifosfamide, and melphalan are part of which subgroup and which class of agents?

Answer 7

Nitrogen mustard gas derivatives in alkylating agents

Question 8

Which are following are notable toxicities for cyclophosphamide? Select all that apply
A) N/V/D
B) Hemorrhagic cystitis 
C) Leukopenia
D) SIADH

Answer 8

B, C, D

Question 9

What are ways to reduce incidence of hemorrhagic cystitis when administering cyclophosphamide? Select all that apply
A) Hyperhydration
B) Mesna
C) Continuous bladder irrigation
D) Pre-med with steriods, antihistamines, APAP

Answer 9

A B C

Question 10

Cyclophosphamide metabolism occurs more quickly than ifosfamide even though it is a prodrug, and its dose limiting toxicity is hemorrhagic cystitis. True or False?

Answer 10

False. Cyclophosphamide’s dose limiting toxicity is leukopenia

Question 11

What are Ifosfamide's 2 dose limiting toxicities?
A) Hemorrhagic cystitis
B) Leukopenia
C) Neurotoxicity 
D) HFS

Answer 11

A & C

Question 12

Ifosfamide is a prodrug requiring metabolic activation, but it has a slower activation rate resulting in more prolonged exposure to the bladder. True or False?

Answer 12

True

Question 13

Match the metabolite. \_\_\_\_ is the toxic metabolite in both cyclophosphamide and ifosfamide causing hemorrhagic cystitis, while \_\_\_\_ is the toxic metabolite only found with ifosfamide causing dose limiting neurotoxicity -- encephalopathy--and renal tubular damage. 
A) Aldophosphamide, Acrolein
B) Acrolein, Chloroacetaldehyde
C) Chloroacetaldehyde, Acrolein
D) Nitrogen mustard, Acrolein

Answer 13

B

Question 14

What is the mandatory administration agent needed with Ifosfamide?
A) Hyperhydration
B) Pre-meds 
C) Continuous bladder irrigation
D) Mesna

Answer 14

D because it is a disulfide detoxifier to help make acrolein a non toxic compound

Question 15

Ifosfamide is considered a bifunctional alkylating agent that alkylates both DNA and RNA. True or false?

Answer 15

False, Melphalan does this

Question 16

Which the following is a false statement about Melphalan?
A) The dose limiting toxicities are bone marrow suppression and mucositis.
B) It requires mesna to reduce risk of hemorrhagic cystitis
C) As an alkylating agent, it is recognized as carcinogenic
D) It has potent ability to ablate bone marrow and has potent immunosuppressive effects
E) As a bifunctional alkylating agent, it can cause intrastrand linking and cross linking

Answer 16

B. This is true for Ifosfamide (mandatory administration) and cyclophosphamide (along with hyperhydration and continuous bladder irrigation)

Question 17

Busulfan is the only one in its subgroup of alkylsulfonate, and it can cross link between DNA strands. True or false?

Answer 17

True

Question 18

What are the main toxicities related to Busulfan? Select all that apply
A) Neurotoxicitiy/Seizures
B) Liver toxicity/VOD/SOS
C) Pulmonary fibrosis and injury
D) Severe myelosuppression

Answer 18

All of the above
A) Neurotoxicitiy/Seizures: readily penetrates brain and CSF
B) Liver toxicity/VOD/SOS: extensive hepatic metabolism
C) Pulmonary fibrosis and injury: high concentrations in lungs
D) Severe myelosuppression: high concentration in bone marrow

Question 19

Busulfan is based on a trough-based dosing for closer monitoring because low exposures are associated with relapses while high exposures are associated with liver toxicity and other fatal adverse effects. True or False?

Answer 19

False. AUC dosing

Question 20

Why would Bulsulfan have DDIs with azoles, metronidazole, APAP, and phenytoin?
A) Because they got beef with everyone
B) It has extensive renal metabolism 
C) It has extensive hepatic metabolism 
D) It goes through p-gp enzymes

Answer 20

C = potential CYP/GST DDIs

Question 21

Triazenes - Dacarbazine and Temozolamide - can do methylation and cross linking. True or False?

Answer 21

False. Only methylation. 3 adjacent nitrogens are responsible for the alkylation/methylation activity `

Question 22

Dacarbazine can be best described by which of the following statements:
A) 100% oral bioavailability that can easily cross the BBB
B) Spontaneously forms MTIC in cellular pH to cause methylation that leads to apoptosis
C) Methylation of DNA generates base/base mismatches with cytosine and thymine
D) All of these are true about Dacarbazine

Answer 22

C; A & B describe Temozolomide

Question 23

Temozolamide of the triazene class within alkylating agents can cause NV, loss of appetite/anorexia, and neuropathy. True or False?

Answer 23

False; Dacarbazine does

Question 24

Carboplatin, Cisplatin, and Oxaliplatin are all considered alkylating agents. True or False?

Answer 24

False. They do not have an alkyl group but they damage DNA in a similar manner. They are considered metal salts (including platinum analogs)

Question 25

What is the MOA of Carboplatin, Cisplatin and Oxaliplatin? A) Crosslinking and Methylation B) Crosslinking (inter- and intra-strand linking) C) Intra-strand linking only D) Methylation

Answer 25

B: Cross linking between DNA strands by replacing chloride ligands with water molecules so they can covalently bind to DNA bases.

Question 26

Platinum agents are most well known to have adverse effects of nephrotoxicity, neurotoxicity, and emetogenic. What is the order of highest to least concern? A) Amifostine > Cisplatin > Carboplatin B) Cisplatin > Carboplatin > Oxaliplatin C) Oxaliplatin > Carboplatin > Cisplatin D) Carboplatin > Amifostine > Oxaliplatin

Answer 26

B

Question 27

Cisplatin accumulates in the kidney cells and cochlear hair cells, causing ototoxicity & tinnitus unique to cisplatin. True or False?

Answer 27

True

Question 28

What supportive care measures that need to be taken while administering Cisplatin? Select all that apply A) Mesna, hyperhydration, continuous bladder irrigation B) Forced diuresis and replaced Mg, K, and Ca C) Mesna only D) None. It is well tolerated.

Answer 28

B. Forced diuresis to reduce nephrotoxicity and replace Mg, K, Ca due to renal tubular damage

Question 29

``` Fill in the blank: ____ is used to reduce cumulative renal toxicity with cisplatin because it traps alkylating electrophiles and scavenges free radicals. A) Mesna B) Leucovorin C) Glucarpidase D) Amifostine ```

Answer 29

D : prodrug into a cytoprotective thiol metobolite

Question 30

``` Carboplatin is generally dose by AUC, and carboplatin is more of which adverse effect than the other agents in its class? A) Ototoxicity B) Emetogenic C) Neurotoxic D) Myelosuppressive ```

Answer 30

D Dose = AUC x [CrCl +25] AUC range 2-6 mg/mL*min

Question 31

``` On ChemoMan, Cisplatin and Carboplatin are seen where? A) Nephrotoxicity and Ototoxicity B) Neurotoxic C) Hemorrhagic cystitis D) Peripheral neuropathy ```

Answer 31

A

Question 32

``` Which third generation platinum causes cumulative peripheral neurotoxicity and neurotoxicity? A) Cisplatin B) Carboplatin C) Oxaliplatin D) Ifosfamide ```

Answer 32

C

Question 33

Carboplatin causes peripheral neuropathy that causes DNA damage-induced apoptosis of dorsal root ganglion neurons and mitochondrial dysfunction. True or false?

Answer 33

False. Oxaliplatin

Question 34

Oxaliplatin has which of the following unique side effect within the platinum agents? A) Ototoxicity B) Cold sensitivities/pain in distal extremities and throat pain C) Extreme N/V/D D) A & B

Answer 34

B

Question 35

``` Because alkylating agents greatly affect rapidly dividing cells, there are significant toxicities in the... A) Hair follicles B) Bone marrow C) Gut lining D) A and B only E) All of the above ```

Answer 35

E