- Alkylating antineoplastic agent
An alkylating antineoplastic agent is an
alkylating agentthat attaches an alkyl group to DNA.
cancercells generally proliferate unrestrictively more than healthy cells do, cancer cells are more sensitive to DNA damage - such as being alkylated. Alkylating agents are used clinically to treat a variety of tumours.
Agents acting nonspecifically
Some alkylating agents are active under conditions present in cells; and the same mechanism that makes them toxic allows them to be used as anti-cancer drugs. They stop tumour growth by cross-linking
guanine nucleobases in DNAdouble-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically.
Agents require activation
Some of them require conversion into active substances "in vivo" (e.g.
cyclophosphamide). Cyclophosphamideis one of the most potent immunosuppressive substances. In small dosages, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosisand other autoimmune diseases. High dosages cause pancytopeniaand hemorrhagic cystitis.
Dialkylating agents, limpet attachment, and monoalkylating agents
"Dialkylating agents" can react with two different 7-N-guanine residues and if these are in different strands of DNA the result is cross-linkage of the DNA strands, which prevents uncoiling of the DNA double helix. If the two guanine residues are in the same strand the result is called "limpet attachment" of the drug molecule to the DNA.
"Monoalkylating agents" can react only with one 7-N of guanine.
Limpet attachment and monoalkylation do not prevent the separation of the two DNA strands of the double helix but do prevent vital DNA processing
enzymes from accessing the DNA. The final result is inhibition of cell growth or stimulation of apoptosis, cell suicide.
Anatomical Therapeutic Chemical Classification System, alkylating agents are classified under L01A.
Alkylating agents activated by cytochrome p-450:
*Ethyleneimines and methylmelamines
**Hexamethylmelamine or altretamine (ATC|L01|XX03)
Mechlorethamineor mustine (ATC|L01|AA05)
Uramustineor uracil mustard (no ATC code, PubChem|6194, DrugBank|APRD00130)
*Platinum-based chemotherapeutic drugs (termed platinum analogues) destroy cells by alkylation. These include:
* [http://pharmacology.unmc.edu/cancer/alkylate.htm University of Nebraska page on alkylating agent drugs]
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