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alkylating agents

Sunday 12 March 2006

Definition: Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. Cisplatin and carboplatin, as well as oxaliplatin, are alkylating agents. Other agents are mechlorethamine, cyclophosphamide, chlorambucil. They work by chemically modifying a cell’s DNA.

Alkylating agents stop tumour growth by cross-linking 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 acts mainly nonspecifically, some of them requires conversion into active substances in vivo (e.g. cyclophosphamide). Since cancer cells generally divide more rapidly than do healthy cells they are more sensitive to DNA damage, and alkylating agents are used clinically to treat a variety of tumours.

- 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 stands 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.

Alkylating agents

- alkyl-sulfonates

  • busulfan

- ethyleneimines and methylmelamines

  • hexamethylmelamine or altretamine
  • thiotepa

- nitrogen mustards

  • cyclophosphamide
  • mechlorethamine (mustine)
  • ramustine (uracil mustard)
  • melphalan
  • chlorambucil
  • ifosfamide

- nitrosoureas

  • carmustine
  • streptozocin

- triazenes

  • dacarbazine
  • temozolomide

Alkylating-like agents

Platinum-based chemotherapeutic drugs (termed platinum analogues) act in a similar manner. These agents don’t have an alkyl group, but nevertheless damage DNA. 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.

- platinum
- cisplatin
- carboplatin
- nedaplatin
- oxaliplatin
- satraplatin
- triplatin tetranitrate

Nonclassical alkylating agents

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

- procarbazine
- altretamine

History

- The discovery of alkylating agents was the consequences of chemical warfare during World Wars I and II that spawned the modern era of cancer chemotherapy. For example, observations made by physicians treating mustard-gas victims of a World War II tragedy led to important clinical insights.

A German bombing raid on the coastal waters of Italy in December 1943 resulted in the sinking of an American ship that contained mustard-gas bombs. This gas, when mixed with fuel oil, dispersed on the surface of the water; men exposed to this mixture soon showed lymphotoxic symptoms.

- Although sulphur mustards were first used in chemical warfare, it was the more stable nitrogen mustards that were developed for cancer chemotherapy. Research before and during World War II led to an appreciation of the biological effects of the nitrogen mustards.

- In 1946, Alfred Gilman and Frederick Phillips correctly determined that the toxic effects were due to alkylation. They reported that the side effects of exposure to nitrogen mustard - nausea, vomiting and myelosuppression - resembled those from exposure to X-rays.

- As these specific organ toxicities are related to the high proliferative rates of these tissues (epithelia of the gastrointestinal tract and bone-marrow cells), it seems likely that cancers such as leukaemias and lymphomas, which also have high proliferative rates compared with most normal tissues, might be particularly susceptible to these agents.

- Indeed, nitrogen mustards caused remissions when they were used to treat lymphomas, and this marked the beginning of the modern era in cancer chemotherapy.

- So, it was established that cancers with high proliferative rates could be treated with alkylating agents, such as the nitrogen mustards, and that their selectivity was dependent on quantitative differences in the rates of division between cancer and normal cells: side effects were most often associated with normal tissues that shared these characteristics.

- Over the next two decades, a wide range of alkylating agents were synthesized in an attempt to control their inherent chemical reactivities. Temozolomide, which is a monoalkylation drug, methylates guanine residues in DNA following a DNA-facilitated rearrangement. The most potent and efficacious agents, however, such as chlorambucil and mephalan, were found to crosslink the two complementary strands of DNA, rather than just alkylating one strand.

- More recently, imaginative approaches to targeting specific cancer types by site-specific delivery or metabolic activation have been used.