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Flashcards in DNA Cross Linking Agents Deck (28)
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0
Q

Nitrosoureas (3)

A

Carmustine
Lomustine
Streptozocin

1
Q

Nitorgen Mustards (6)

A
Mechlorethamine 
Chlorambucil 
Bendamustine 
Melphalan 
Cylcophosphamide 
Ifosfamide
2
Q

Alkylsulfonates

A

Busulfan

3
Q

Methylators (3)

A

Procarbazine
Dacarbazine
Temozolomide

4
Q

Organoplatinum compounds (3)

A

Cisplatin
Carboplatin
Oxaliplatin

5
Q

DNA cross linking agents are divided into…

A

DNA alkylating agents and organoplatinum compound

6
Q

DNA cross linking agents general properties

A

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

7
Q

Nitrogen mustards R group

A

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

8
Q

Mechlorethamine

A

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

9
Q

Water and nitrogen mustards

A

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

10
Q

Chlorambucil

A

Good oral bioavailability -Decreased with food

Toxicity: can induce leukemia

11
Q

Bendamustine

A

Nitrogen mustard plus Antimetabolite

IV

12
Q

Melphalan

A

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

13
Q

Cyclophosphamide

A

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

14
Q

Acrolein metabolite

A

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

15
Q

Ifosfamide

A

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

16
Q

Nitrosoureas

A

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

17
Q

Streptozocin

A

Glycosylated nitrosourea

  • Affinity for islet cell*
  • Dose related nephrotoxicity*
18
Q

Busulfan

A

PO or IV

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

19
Q

Methylators MOA

A

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)

20
Q

Procarbazine

A
  • diazine
  • Methyl radical is methylating species*
  • DDI: inhibits MAOIs, inhihibits enzymes in alcohol metabolism (disulfiram rxn)
21
Q

*Decarbazine

A
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
22
Q

*Temozolamide

A
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
23
Q

Cisplatin: Organoplatinum compound

A

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

24
Q

Carboplatin

A

Less reactive than cisplatin

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

25
Q

Oxaliplatin

A

Not as active as cisplatin

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

26
Q

Water and organoplatins

A

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

27
Q

Mechanism of resistance to alkylating agents

A
  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)