Alkylating antineoplastic agent
An alkylating antineoplastic agent is an
The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring.[citation needed]
Since
History
Before their use in chemotherapy, alkylating agents were better known for their use as
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
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).
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
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
The following three groups are almost always considered "classical".
- Nitrogen mustards[7]
- Cyclophosphamide — the most widely used alkylating agent of modern times.
- Chlormethine also known as mechlorethamine or mustine (HN2) — the first alkylating agent to receive regulatory approval.
- Uramustine or uracil mustard
- Melphalan
- Chlorambucil
- Ifosfamide
- Bendamustine
- Nitrosoureas
- Carmustine
- Lomustine
- Streptozocin
- Alkyl sulfonates
Alkylating-like
- Platinum[7]
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:
- Procarbazine[9]
- Altretamine[10]
- Some sources explicitly exclude the triazenes (dacarbazine, mitozolomide, temozolomide) from the nonclassical category.[11] However, other sources list dacarbazine as nonclassical,[12] and some include temozolomide.[13]
- The platinum agents are also sometimes described as nonclassical.[14]
Limitations
Alkylating antineoplastic agents have limitations. Their functionality has been found to be limited when in the presence of the DNA-repair enzyme
See also
References
- ^ "Alkylating Agents". US National Library of Medicine. Archived from the original on 16 October 2014. Retrieved 2 August 2014.
- PMID 20997191.
- ^ PMID 4319950.
- PMID 13947966.
- ISSN 0009-2665.
- PMID 10500495.
- ^ 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.
- PMID 18289945.
- PMID 18360630.
- ISBN 0-443-06527-6.
- ISBN 3-540-66508-0.
- ISBN 0-632-03998-1.
- ISBN 0-07-147781-0.
- ISBN 0-7817-5492-5.
- ^ N Engl J Med 2000;343;1350-4.
External links
- University of Nebraska page on alkylating agent drugs
- Alkylating+antineoplastic+agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Cancer Management Handbook: Principles of Oncologic Pharmacotherapy Archived 2009-05-15 at the Wayback Machine