DNA Cross Linking Agents Flashcards
Nitrosoureas (3)
Carmustine
Lomustine
Streptozocin
Nitorgen Mustards (6)
Mechlorethamine Chlorambucil Bendamustine Melphalan Cylcophosphamide Ifosfamide
Alkylsulfonates
Busulfan
Methylators (3)
Procarbazine
Dacarbazine
Temozolomide
Organoplatinum compounds (3)
Cisplatin
Carboplatin
Oxaliplatin
DNA cross linking agents are divided into…
DNA alkylating agents and organoplatinum compound
DNA cross linking agents general properties
Cell cycle non specific
Cytotoxic, mutagenic, teratogenic, myelosuppressive
Acute toxicity: N/V, myelosuppression
Nitrogen mustards R group
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
Mechlorethamine
R group is methyl (aliphatic), fast formation of aziridinium ion
IV administration can cause extravasation
Toxicity: *vesicant (inactivate w/ thiosulfate), * highly emetogenic
Water and nitrogen mustards
Water can act as a nucleophile and attack/inactivate nitrogen mustard. Formulate preparation in a slightly acidic pH to decrease nucleophilic nature of water
Chlorambucil
Good oral bioavailability -Decreased with food
Toxicity: can induce leukemia
Bendamustine
Nitrogen mustard plus Antimetabolite
IV
Melphalan
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
Cyclophosphamide
PRODRUG
Oral or IV
Acrolein metabolite= uro- & nephrotoxic
Chloroacetaldehyde= neuro- & nephrotoxic
Protonated 4’ aziridine major active metabolite
Acrolein metabolite
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
Ifosfamide
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
Nitrosoureas
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
Streptozocin
Glycosylated nitrosourea
- Affinity for islet cell*
- Dose related nephrotoxicity*
Busulfan
PO or IV
*Toxicity: pulmonary fibrosis, adrenal insufficiency, myelosuppression, busulfan tan
Methylators MOA
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)
Procarbazine
- diazine
- Methyl radical is methylating species*
- DDI: inhibits MAOIs, inhihibits enzymes in alcohol metabolism (disulfiram rxn)
*Decarbazine
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
*Temozolamide
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
Cisplatin: Organoplatinum compound
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
Carboplatin
Less reactive than cisplatin
Toxicity: *myelosuppression, FEWER non-hematologic toxicities (nephro-& neurotoxicities)
Oxaliplatin
Not as active as cisplatin
Toxicity: neurotoxicity (reversible), paraesthesia (triggered or worsened by cold)
Water and organoplatins
Water activates platins. Platinum is electron deficient (electrophile) and water acts as nucleophilic.
Mechanism of resistance to alkylating agents
- Decreased permeation of actively transported drugs
- Increased intracellular concentration of detoxifying substances (glutathione)
- Increased activity if DNA repair pathways (o-alkyltransferase)
- Increased rates of drug inactivation (aldehyde dehydrogenase)