Alkylating antineoplastic agent

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An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (C_nH_2n+1) to DNA.^[1]

The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.

Since cancer cells, in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage — such as being alkylated. Alkylating agents are used to treat several cancers. However, they are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently, as those in the gastrointestinal tract, bone marrow, and ovaries, which can cause loss of fertility. Alkylating agents are also carcinogenic. Hyperthermia is especially effective at enhancing the effects of alkylating agents.^[2]

History

Before their use in chemotherapy, alkylating agents were better known for the use of sulfur mustard ("mustard gas") and related chemical weapons in World War I. In general, these were not used in World War II, but, in a lone exception, the United States Liberty Ship John Harvey carried a cache of the weapons that were released during the Air Raid on Bari in 1943, causing casualties to hundreds of sailors and Italian civilians. Medical tests of affected personnel revealed a profound bone marrow and lymphoid aplasia. Nitrogen mustard was subsequently recommended for testing in humans by Goodman and Gilman at Yale. Because of secrecy surrounding the war gas program, the results were not published until 1946,^[3] but revealed a striking but temporary dissolution of tumor masses. Even so, it was not until 1963 that further studies of the drug began to impact patients.^[4]

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.

Agents require activation

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

Cyclophosphamide is 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 granulomatosis, and other autoimmune diseases. High dosages cause pancytopenia and 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.

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.^[5]

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

• Nitrogen mustards^[6]
  • Cyclophosphamide
  • Mechlorethamine or mustine (HN2)
  • Uramustine or uracil mustard
  • Melphalan
  • Chlorambucil
  • Ifosfamide

• Nitrosoureas
  • Carmustine
  • Lomustine
  • Streptozocin

• Alkyl sulfonates
  • Busulfan

Thiotepa and its analogues are usually considered classical, but can be considered nonclassical.

Alkylating-like

Platinum-based chemotherapeutic drugs (termed platinum analogues) act in a similar manner. These agents do not have an alkyl group, but nevertheless damage DNA.^[7] They permanently coordinate to DNA to interfere with DNA repair, so they are sometimes described as "alkylating-like".

• Platinum^[6]
  • Cisplatin
  • Carboplatin
  • Nedaplatin
  • Oxaliplatin
  • Satraplatin
  • Triplatin tetranitrate

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^[8]

• altretamine^[9]

• Some sources explicitly exclude the tetrazines (dacarbazine, mitozolomide, temozolomide) from the nonclassical category.^[10] However, other sources list dacarbazine as nonclassical,^[11] and some include temozolomide.^[12]

• The platinum agents are also sometimes described as nonclassical.^[13]

References

External links

• University of Nebraska page on alkylating agent drugs
• MeSH Alkylating+antineoplastic+agents
• Cancer Management Handbook: Principles of Oncologic Pharmacotherapy