Alkylating antineoplastic agent

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An alkylating antineoplastic agent is an

alkyl group (CnH2n+1) to DNA.[1]

The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring.[citation needed]

Since

carcinogenic
.

History

Before their use in chemotherapy, alkylating agents were better known for their use as

mechlorethamine, mustine) and tris (B-chloroethy) amine hydrochloride for Hodgkin's disease lymphosarcoma, leukemia, and other malignancies resulted in striking but temporary dissolution of tumor masses. Because of secrecy surrounding the war gas program, these results were not published until 1946.[2] These publications spurred rapid advancement in the previously non-existent field of cancer chemotherapy, and a wealth of new alkylating agents with therapeutic effect were discovered over the following two decades.[3]

A common myth holds that Goodman and Gilman were prompted to study nitrogen mustards as a potential treatment for cancer following a 1943 incident in

Bari, Italy, where survivors exposed to mustard gas became leukopenic. In fact, animal and human trials had begun the previous year, Gilman makes no mention of such an episode in his recounting of the early trials of nitrogen mustards,[4] and the marrow-suppressing effects of mustard gas had been known since the close of World War I.[3]

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 tumor growth by crosslinking guanine nucleobases in DNA double-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. Electrophilic alkylating agents such as nitrogen mustards, methanesulfonates, and cisplatins tend to act in this manner to produce a variety of DNA damage products such as mono- and dialkylation, inter- and intrastrand crosslinks, and DNA-protein crosslinks.[5]

Agents requiring activation

Some of the substances require conversion into active substances in vivo (e.g., cyclophosphamide).

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

1,4-butanediol. Methanesulfonate can be eliminated as a leaving group
. Both ends of the molecule can be attacked by DNA bases, producing a butylene crosslink between two different bases.

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.

Examples

In the Anatomical Therapeutic Chemical Classification System, alkylating agents are classified under L01A.

Classical alkylating agents

Many of the agents are known as "classical alkylating agents". These include true

alkyl groups, and have been known for a longer time than some of the other alkylating agents. Examples include melphalan and chlorambucil.[6]

The following three groups are almost always considered "classical".

Alkylating-like

alkyl group, but nevertheless damage DNA.[8]
They permanently coordinate to DNA to interfere with DNA repair, so they are sometimes described as "alkylating-like".

These agents also bind at N7 of guanine.

Nonclassical

Certain alkylating agents are sometimes described as "nonclassical". There is not a perfect consensus on which items are included in this category, but, in general, they include:

Limitations

Alkylating antineoplastic agents have limitations. Their functionality has been found to be limited when in the presence of the DNA-repair enzyme

O-6-methylguanine-DNA methyltransferase (MGMT). Cross-linking of double-stranded DNA by alkylating agents is inhibited by the cellular DNA-repair mechanism, MGMT. If the MGMT promoter region is methylated, the cells no longer produce MGMT, and are therefore more responsive to alkylating agents. Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of tumors to alkylating agents.[15]

See also

References

  1. ^ "Alkylating Agents". US National Library of Medicine. Archived from the original on 16 October 2014. Retrieved 2 August 2014.
  2. PMID 20997191
    .
  3. ^ .
  4. .
  5. .
  6. .
  7. ^ a b Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" Archived 2009-05-15 at the Wayback Machine in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach Archived 2013-10-04 at the Wayback Machine. 11 ed. 2008.
  8. PMID 18289945
    .
  9. .
  10. .
  11. .
  12. .
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  14. .
  15. ^ N Engl J Med 2000;343;1350-4.

External links