Types Of Alkylating Agents

Submitted By Nic-DiTommaso
Words: 2360
Pages: 10

Alkylating agents
MOA: alkylate the DNAactivation leads to an intermediate reacting to certain sites on nucleic basesfailure to repair DNA will lead to apoptosis
Notes: suppress the bone marrow cells the most
Toxicities
Bone marrow suppression can give neupogen(filgastrim) or Neulasta (pegfilgrastrim) as prophylaxis
Toxicity prophylaxis( for nephrotoxicity, serostomia, and bone-marrow suppression)
Give Amifostine
Prodrug that is converted by alkaline phosphatase into reactive metabolite that has –SH groups.
Works as a cytoprotective agent to detoxify alkylating agents in normal cells
Resistance:
Over expression of PGP
Enhanced detoxification by glutathione
Enhanced drug metabolism to inactive meatabolites
Enhanced activity of DNA repair mechanisms

Mono-functionalwill generate one reactive intermediate that will exert its effects on DNA bases
Nitrogen-Mustards
Mechlorethamine (Mustargen)
Chlorambucil (Leukeran)
Melphalan (Alkeran)
Cyclophosphamide
PRODRUG that is converted by CYP450 to reactive intermediate that can be detoxified by aldehyde dehydrogenase
Reactive intermediate is broken down into acroleincan lead to hemorraghic cystitiscan give sodium 2-mercaptoethan sulfonate (Mesna) to inactivate acrolein
Ifosfamide
Analog of cyclophosphamide
Bi-functional will generate two reactive intermediates that will damage DNA AND PROTEINS
Nitrosureas
Carmustine (BCNU)
Lomustine (CCNU)
Triazenes
Dacarbazine (DTIC)
Activated by CYP450 to reactive metabolite
Temozolomide
Spontaneously degraded to same reactive metabolite as DTIC

Platinum Compounds
Works similar to alkylating agents except they don’t alkylate the DNA
MOA:
Form covalent bonds with DNA strands
Formation of intra-strand DNA adducts or cross linking DNA strands or DNA to protein
Pt complexes form rxtive intermediate that cross link DNA strands
Drugs
Cisplatin
Forms inter-strand adduct that interferes with DNA repair mechanisms
Interchangeable with only carboplatin
Drug specific ADR
Nephrotoxicity
Due to high expression of OCT-2 and CTR-1 transporters that would allow the uptake of cisplatin on renal tubular cells
Carboplatin
Drug specific ADR
Myelosuppression
Oxaliplatin
Drug specific ADR
Peripheral neuropathy
Cisplatin Mech. of resistance
Decreased expression of Cu transproters
Over expression of PGP
Used verapamil to overcome resistance, but it can casue ADRs on the SA/AV nodes
Increased expression of GST
Nucleotide excision repair
Translesion synthesis/ replicative bypass

Antimetabolites
S-Phase specific
MOA
Blocks the de-nova synthesis of pyrimidine/purine bases
Anti-folates
Methotrexate (MTX)
MOA: MTX gets taken up into the cell and gets polyglutamated by folylpolyglutamate (FPGS)MTXPG inhibits dihydrogolate reductase (DHFR) and thymidylate synthase (TYMS) inhibits DE-NOVO PURINE SYNTHESIS
High dose MTX os potentially legthal if toxic effects of normal cells are not reversed
Use leucovorin(folinic acid) as “MTX rescue”
Resistance
Decreased intra-tumor drug tx
Decresased MTX polyglutamation
Increased DHFR synthesis/DHFR mutation increased drug efflux
Pemetrexed
Multi-targeted enzyme inhibitors  TS, DHFR, & GARFT
GARFT is main difference between PTX and MTX. GARFT will form AMP and GMP
More potent than MTX
Purine Analogs: inhibitors of purine metabolism
MOA:
Get activated by HGPRT
Gets degraded by TPMT into inactive metabolites
pharmacogenomics, people that lake the gene for TPMT will have more toxicities
Drugs
6-mercaptopurine (6-MP)
Activated by HGPRT into T-IMPinhibits AMP/GMP synthesis
It id detoxified by XO, so giving it with allopurinol will increase the levels of 6-MP bc allopurinol is an XO inhibitor
6-thioguanine
Activated by HGPRT into 6-thioGMinhibits GMP synthesis and will incorporate itself into DNA

Antimetabolites (continued)
Purine analogs: incorportation in DNA
MOA:
Work by their ability to block DNa synthesis at the level of the growing strand of DNA WILL CAUSE CHAIN…