DNA Cross Linking Agents

Question 0

Nitrosoureas (3)

Answer 0

Carmustine
Lomustine
Streptozocin

Question 1

Nitorgen Mustards (6)

Answer 1

Mechlorethamine 
Chlorambucil 
Bendamustine 
Melphalan 
Cylcophosphamide 
Ifosfamide

Question 2

Alkylsulfonates

Answer 2

Busulfan

Question 3

Methylators (3)

Answer 3

Procarbazine
Dacarbazine
Temozolomide

Question 4

Organoplatinum compounds (3)

Answer 4

Cisplatin
Carboplatin
Oxaliplatin

Question 5

DNA cross linking agents are divided into…

Answer 5

DNA alkylating agents and organoplatinum compound

Question 6

DNA cross linking agents general properties

Answer 6

Cell cycle non specific
Cytotoxic, mutagenic, teratogenic, myelosuppressive
Acute toxicity: N/V, myelosuppression

Question 7

Nitrogen mustards R group

Answer 7

Influences reactivity, bioavailability, and toxicity
R=aliphatic-> nitrogen more basic, accepts electrons. Aziridinium ion formed faster, more toxicity
R=aromatic-> nitrogen less basic, loses electrons to electron withdrawing groups, resonance delocalization of lone pair. Aziridinium ion formed slower, less toxicity

Question 8

Mechlorethamine

Answer 8

R group is methyl (aliphatic), fast formation of aziridinium ion
IV administration can cause extravasation
Toxicity: *vesicant (inactivate w/ thiosulfate), * highly emetogenic

Question 9

Water and nitrogen mustards

Answer 9

Water can act as a nucleophile and attack/inactivate nitrogen mustard. Formulate preparation in a slightly acidic pH to decrease nucleophilic nature of water

Question 10

Chlorambucil

Answer 10

Good oral bioavailability -Decreased with food

Toxicity: can induce leukemia

Question 11

Bendamustine

Answer 11

Nitrogen mustard plus Antimetabolite

IV

Question 12

Melphalan

Answer 12

Nitrogen mustard w/ L- phenylalanine structure
Makes drug look like amino acid
Oral absorption is erratic, decreased w/ food
Distributes into body water- potential toxicity in dehydrated pts or renal dysfxn
Toxicity: LESS n/v. Can induce leukemia

Question 13

Cyclophosphamide

Answer 13

PRODRUG
Oral or IV
Acrolein metabolite= uro- & nephrotoxic
Chloroacetaldehyde= neuro- & nephrotoxic
Protonated 4’ aziridine major active metabolite

Question 14

Acrolein metabolite

Answer 14

uro- & nephrotoxic-> hemorrhagic cystitis
Normal cells have aldehyde dehydrogenase that convert acrolein to a Carboxylic acid that can be eliminated. Cancer cells are deficient in this enzyme
MESNA (glutathione+ cystine binds acrolein )mitigates urotoxicity

Question 15

Ifosfamide

Answer 15

PRODRUG
Metabolic activation by CYP3A4 to major and active metabolite
*Slower activation bc of steric hindrance requires higher doses than cyclophosphamide and thus increase risk of toxicity
Acrolein metabolite= uro- & nephrotoxicity
Chloroacetaldehyde= neuro- & nephrotoxic
Protonated 3’ aziridine major active metabolite

Question 16

Nitrosoureas

Answer 16

High lipid solubility-> useful for brain tumors
Acts through nitroso group and chloro ethyl group-> bothy vinyl carbocation and 2-chloro ethyl carbocation are alkylating agents
*toxicity: prolonged myelosuppression

Question 17

Streptozocin

Answer 17

Glycosylated nitrosourea

• Affinity for islet cell*
• Dose related nephrotoxicity*

Question 18

Busulfan

Answer 18

PO or IV

*Toxicity: pulmonary fibrosis, adrenal insufficiency, myelosuppression, busulfan tan

Question 19

Methylators MOA

Answer 19

O6-methylation of guanine nucleotides. Guanine mis pairs with thymine instead of pairing w/ cytosine
Resistance mechanism: cancer cells repair O6- methylation by O6-alkyl guanine DNA alkyltransferase (methyl group gets transferred on to enzyme)

Question 20

Procarbazine

Answer 20

• diazine
• Methyl radical is methylating species*
• DDI: inhibits MAOIs, inhihibits enzymes in alcohol metabolism (disulfiram rxn)

Question 21

*Decarbazine

Answer 21

Must be bio transformed to MTIC to act
Triazine=methylcarbocation 
Poor oral absorption-> IV
Hepatic conversion to MTIC
Does NoT cross BBB
Use: malignant melanoma 
Toxicity: myelosuppression, hepatoxocity

Question 22

*Temozolamide

Answer 22

Must be bio transformed to MTIC to act
Triazine=methylcarbocation 
Rapid oral absorption->PO, IV
Non-Hepatic conversion to MTIC
Readily crosses BBB
Use: glioblastoma melanoma 
Toxicity: myelosuppression, hepatoxocity

Question 23

Cisplatin: Organoplatinum compound

Answer 23

MOA: intrastrand DNA cross linking(adjacent guanine residues)
*Toxicity: *dose and duration dependent neurotoxicity (prehydrate w/ saline), *neurotoxicity (ototoxicity and paraesthesia of hands and feet), *emesis, *myelosuppression

Question 24

Carboplatin

Answer 24

Less reactive than cisplatin

Toxicity: *myelosuppression, FEWER non-hematologic toxicities (nephro-& neurotoxicities)

Question 25

Oxaliplatin

Answer 25

Not as active as cisplatin

Toxicity: neurotoxicity (reversible), paraesthesia (triggered or worsened by cold)

Question 26

Water and organoplatins

Answer 26

Water activates platins. Platinum is electron deficient (electrophile) and water acts as nucleophilic.

Question 27

Mechanism of resistance to alkylating agents

Answer 27

1. Decreased permeation of actively transported drugs
2. Increased intracellular concentration of detoxifying substances (glutathione)
3. Increased activity if DNA repair pathways (o-alkyltransferase)
4. Increased rates of drug inactivation (aldehyde dehydrogenase)