Alkylants

Alkylating cytostatics or alkylating agents are highly reactive substances that bind covalently to nucleophilic groups (e.g. amino, carboxyl, hydroxyl, phosphate and sulfhydryl groups) of DNA, RNA or proteins and transfer alkyl residues (mainly methyl and ethyl groups) to them. In higher concentrations, alkylating agents can also break the covalent bonds within the DNA strands.

Bifunctional alkylating agents, i.e. those with two or more functional groups, can cause a covalent linkage of DNA bases within a strand ("intrastrand cross-link") or between the strands ("interstrand cross-link"). Strand breaks and cross-links cause far more serious damage to the DNA, and therefore to the cell, than monofunctional alkylations.

The high reactivity of these compounds, which are associated with considerable side effects, led to the development of the oxazaphosphorins cyclophosphamide and ifosfamide, which are transport forms of a "prodrug". These compounds require enzymatic activation by cytochrome P-450-dependent monooxygenases to develop their therapeutic activity. Bifunctional alkylants also include platinum complexes and mitomycins, whose ability to form cross-links has been experimentally proven.

Nitrogen-Lost-Derivatives (Lost= abbreviation of the names of the developers Lommel and Steinkopf)

• Cyclophosphamide
• Ifosfamide
• Trofosfamide
• Chlorambucil
• Melphalan
• Estramustin
• Bendamustin

Ethyelnimines

• Thiotepa(tetraethylene pentamine)

Sulphonic alkyl ester

• Busulfan

Nitrosourea

• Carmustine (BCNU)
• Lomustine (CCNU)

Platinum compounds

• Cisplatin
• Carboplatinum
• Oxaliplatin

Hydrazines

• Dacarbazine
• Procarbazine
• Temozolomide

The drug effects of cytostatic drugs are thus based on an inhibition of DNA replication. Alkylants are mutagenic and carcinogenic. They are used in toxicology as a reference for carcinogenicity testing. Even though alkylants have been further developed over the years, it is clear on critical examination that the specificity of these therapeutics has not yet been significantly improved.

Alkylancias are used in lymphomas, leukaemia, breast and lung cancer and sarcomas. Nitrogen-Lost has been used for a long time (mainly in the USA) in the external therapy of cutaneous T-cell lymphomas. They are particularly important in the treatment of malignant brain tumours (gliobalstomes).

The most common adverse drug reactions include hair loss, nausea, vomiting, anemia and immunosuppression. The destructive effect on DNA affects mainly fast growing cell lines such as mucous membrane, hair root, gonadal epithelia and bone marrow cells (myelotoxic). They can also have nephrotoxic, ototoxic and neurotoxic effects (central and peripheral neuropathies).

1. Meyer U (2006): The history of alkylancias. Pharmacy in our time 35: 104 - 109