Alkylating agents
As alkylating agents (obsolete also alkylating agents , singular: the alkylating agent ) may be chemical alkylating agent referred to the alkyl groups in the DNA insert. This creates DNA adducts . As DNA damage , they interfere with DNA methylation, among other things, and can permanently change genetic information. Mutations sometimes occur due to faulty DNA repair . In higher concentrations, they lead to strand breaks in the DNA. Bifunctional alkylating agents can also chemically permanently link two DNA strands. All alkylating agents are potentially mutagenic and carcinogenic .
Alkylating agents are used as cytostatics (drugs for chemotherapy for the treatment of cancer ) as well as in water treatment and in the food industry as cold disinfectants and in molecular biology as ribonuclease inhibitors.
history
During the First World War , doctors discovered that the battle gas sulfur mustard (mustard gas) had an antiproliferative (growth-inhibiting) effect. After the war, the less toxic nitrogen mustard ( mechlorethamine ) was developed and used as the first cytostatic drug in medicine around 1942 . To date, nitrogen mustard is permitted in the USA ; its derivatives are included in numerous modern treatment regimens.
In search of a water sanitizing agent for drinking water contaminated with bacteria, diethyl dicarbonate was developed during World War II . Due to its toxicity, it was not able to establish itself permanently in this application. However, it is still used in molecular biology to inactivate ribonucleases (RNases). In addition, diethyl dicarbonate was used in the beverage industry for the so-called cold pasteurization of fruit juices, wine and beer ( cold sterilization ). However, in the presence of ammonium ions (NH 4 + ) in aqueous-acidic solution, it can form O - ethyl carbamate , which is hazardous to health . For this reason, the addition of diethyl dicarbonate to beverages was banned in Germany in 1973. Dimethyl dicarbonate is used as a secondary active ingredient .
function
At certain concentrations, alkylating agents develop a cytotoxic effect. If a certain degree of alkylation of the DNA is exceeded, the cell cycle is stopped at a checkpoint due to the detected DNA damage and the affected cell no longer divides.
In higher concentrations, alkylating agents can also break the covalent bonds within the DNA strands. Bifunctional alkylating agents, d. H. those that are provided with two or more functional groups can also link two DNA strands using covalent chemical bonds ( crosslinks ). Strand breaks and crosslinks represent far more serious damage to DNA, and thus to the cell, than monofunctional alkylations. In much lower concentrations, both prevent the correct replication of the affected DNA during cell division and lead to the arrest of the cell cycle.
The medicinal effects of the cytostatics are based on a combination of these effects. They are still often used for lymphoma , leukemia , breast and lung cancer and sarcoma . They are of particular importance against malignant brain tumors .
Side effects
The problem with fighting cancer cells is to differentiate them pharmacologically from other body cells in order to be able to fight them in a targeted manner. One characteristic that sets cancer cells apart from most, but not all, other cells in the body is that they grow rapidly and divide frequently. Cancer cells have a high rate of cell division. This is where cytostatics come into play. The mode of action of the alkylating agents ensures that all body cells that are currently in the cell division phase and into which the drug has penetrated are destroyed.
The destructive effect on DNA thus affects all cells in the body, but most frequently dividing cells, such as B. cells of the mucous membranes , hair roots , gonads and bone marrow . During chemotherapy, besides the cancer cell tissue, the tumor or the metastases, these tissues are particularly affected.
Their main side effects can be attributed to the impairment of these tissues and are nausea, anemia , immunodeficiency , dry mucous membranes, hair loss, etc. Due to the fact that alkylating agents are also mutagenic, the hair that grows back after chemotherapy is discontinued may be different Have hair color.
When using dimethyl dicarbonate as a cold disinfectant, small amounts of O- methyl carbamate are formed , which has been shown to be carcinogenic in various studies. It's on the California state's list of cancer-causing substances.
Active ingredient families
- Cytostatics
-
- - Cyclophosphamide , ifosfamide , mafosfamide , trofosfamide
- - Bendamustine , chlorambucil , melphalan , mechlorethamine
- - Estramustine (alkylating group attached to estradiol )
- - busulfan , treosulfan
- - Carmustine , Lomustine , Nimustine
- Cold disinfectants (also ribonuclease inhibitors)
- Other alkylating mutagens
- with increased sequence specificity
literature
- Ulrich Meyer: The history of alkylating agents . In: Pharmazie in our time 35 (2), pp. 104-109 (2006).
Web links
- www.brustkrebs-info.de - alkylating agents
Individual evidence
- ↑ Summers, WC (1970): A simple method for extraction of RNS from E. coli utilizing diethyl pyrocarbonate. In: Anal. Biochem. 33 (2): 459-463. PMID 4910776 .
- ↑ Entry on urethane. In: Römpp Online . Georg Thieme Verlag, accessed on June 8, 2014.
- ↑ National Toxicology Program: Toxicology and Carcinogenesis Studies of Methyl Carbamate (CAS No. 598-55-0) in F344 / N Rats and B6C3F1 Mice (Gavage Studies). In: National Toxicology Program technical report series. Volume 328, November 1987, pp. 1-176. PMID 12732908 .
- ^ The Proposition 65 List. In: oehha.ca.gov. Office of Environmental Health Hazard Assessment , accessed February 25, 2017 .
- ↑ C. Suckling: From multiply active natural product to candidate drug? Antibacterial (and other) minor groove binders for DNA. In: Future Medicinal Chemistry . Volume 4, Number 8, May 2012, pp. 971-989. doi: 10.4155 / fmc.12.52 . PMID 22650239 .
- ↑ KS MacMillan, T. Nguyen, I. Hwang, DL Boger: Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin. In: Journal of the American Chemical Society . Volume 131, Number 3, January 2009, pp. 1187-1194. doi: 10.1021 / ja808108q . PMID 19154178 . PMC 2646182 (free full text).
