ATC Group: L01A Alkylating agents

Bendamustine is an alkylating antitumour agent with unique activity. The antineoplastic and cytocidal effect of bendamustine is based essentially on a cross-linking of DNA single and double strands by alkylation. As a result, DNA matrix functions and DNA synthesis and repair are impaired.

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.

Carboquone is an anticancer alkylating agent, having chemical structure, 2,5-bis-(1-aziridinyl)3(2-carbamoyloxy-1-methoxyethyl)-6-methyl- 1,4- benzoquinone. The antitumor efficacies of carboquone were reported as excellent, however, the side effects are considerably strong.

Carmustine is a cell-cycle phase nonspecific antineoplastic agent of the nitrosourea type. As an alkylating agent, it can alkylate reactive sites on nucleoproteins, thus interfering with DNA and RNA synthesis and DNA repair. In addition, carmustine is known to carbamoylate lysine residues on proteins causing irreversible inactivation of enzymes including glutathione reductase.

Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent. In addition to interference with DNA replication, chlorambucil induces cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of an apoptosis promoter.

Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. It has been derivatized into the estrogen analogue estramustine phosphate, used to treat prostate cancer.

Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types. The active metabolites of cyclophosphamide are alkylating agents which transfer alkyl groups to DNA during the process of cell division, thus preventing normal synthesis of DNA.

Dacarbazine is a cytostatic agent. The antineoplastic effect is due to an inhibition of cell growth which is independent of the cell cycle and due to an inhibition of DNA synthesis.

Fotemustine is a chloroethylating nitrosourea with antineoplastic activity. Fotemustine alkylates guanine by forming chloroethyl adducts at the 6 position of guanine, resulting in N1-guanine and N3-cytosine cross linkages, inhibition of DNA synthesis, cell cycle arrest, and finally apoptosis. This agent is lipophilic and crosses the blood-brain barrier.

Ifosfamide is an antineoplastic, a cytotoxic alkylating agent. It is a prodrug and shows no in vitro cytotoxic activity until activated by microsomal enzymes. The cytotoxic activity of ifosfamide (alkylation of the nucleophilic centres in the cells) is associated with the activated oxazaphosphorine ring hydroxylated at the C4 atom which interacts with DNA-DNA cross linking. This activity manifests itself by blocking the late S and early G2 phases of the cell cycle.

Lomustine’s mode of action is believed to be partly as an alkylating agent and partly by inhibition of several steps in the synthesis of nucleic acid and inhibition of the repair of single strand breaks in DNA chains.

Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking the two DNA strands and thereby preventing cell replication.

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O⁶ position of guanine with additional alkylation also occurring at the N⁷ position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene imine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylation of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating alkylated guanine.

Treosulfan is a prodrug of a bifunctional alkylating agent with cytotoxic activity to haematopoietic precursor cells. The activity of treosulfan is due to the spontaneous conversion into a mono-epoxide intermediate and L-diepoxybutan. Treosulfan has a broad antineoplastic and antileukaemic activity.