CLASSIFICATION OF CYTOTOXIC DRUGS, MODE OF ACTION, TOXICITIES AND CLINICAL UTILITY

Historically, anti-cancer agents have been divided into groups according to the mechanism of cytotoxicity. However, the increasing number of new drugs, and their diverse and novel mechanisms of action, make such divisions increas­ingly difficult and arbitrary.

DNA alkylators

The alkylating agents were the first compounds identified to have activity against neoplastic diseases, and have been in use now for more than 50 years. Early studies used the nitrogen mustard mechlorethamine, following observa­tions from the mustard gas chemical warfare programme that soldiers exposed to this agent developed aplasia of the bone marrow. Mechlorethamine was subsequently found to induce significant tumour regression in patients with lymphoma in clinical trials.

Mechlorethamine is ideally suited to illustrate the chemistry of alkylation, having the simplest structure of the class. The - CH₂CH₂Cl linked to nitrogen is labelled the mustard group, and in the case of mechlorethamine there are two such groups, thus giving the term ‘bifunctional nitrogen mustard’. Following administration, the drug undergoes an internal cyclization reaction and loses a chlo­ride ion to form an electron-deficient, positively charged azindinium ion. These highly reactive species are able to react and form covalent bonds (adducts) with electron-rich (nucleophilic) sites in DNA, such as the 7-nitrogen group of guanine on the major groove. Other biological macromolecules, e.g. proteins, are also targeted, but it is the reactions involving the nitrogenous bases in DNA that are critical for the anti-cancer action of the alkylating agents. Adduct formation with two separate bases on the DNA, especially across the two anti-parallel strands - the inter-strand crosslink - is thought to be the most lethal interaction. The results of DNA alkylation involve inter­ference with the fidelity of replication and transcription by abrogating the functions of DNA and RNA polymerases. It follows that alkylating agents are most toxic to rapidly cycling cells; tumours with a high fraction of cells in S phase are more vulnerable, possibly as they have less damage-repair time. In addition, adduct formation leads to struc­tural lesions, which include ring opening and base deletions. Cellular repair processes attempt to restore the integrity of the DNA, but if incomplete can result in further damage, such as the creation of apurinic sites or strand breaks. Furthermore, it appears that these repair processes can be saturated by higher doses of alkylating agents, thus providing a rationale for extending the use of these agents into high-dose chemotherapy techniques.

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Anti-metabolites

Anti-metabolites interfere with key steps in normal cellular metabolism due to their similarity of structure to certain RNA and DNA precursors. They can act as substrates for key enzymes, or inhibit enzymic reactions crucial to the synthesis of RNA and DNA, and are therefore S-phase specific. ANTI-FOLATES

Methotrexate primarily inhibits dihydrofolate reductase (DHFR), an enzyme that functions to catalyse the conver­sion of dihydrofolate to tetrahydrofolate, which, in turn, is converted to a variety of co-enzymes involved in reactions in which the carbon atom is transferred in the synthesis of thymidylate, purines, methionine and glycine. By abrogat­ing thymidylate monophosphate synthesis, methotrexate inhibits RNA and DNA synthesis. Folic acid (also known as leucovorin), given orally or intravenously, is converted to the tetrahydrofolate co-enzymes that are needed for the function of thymidylate synthase (TS). This is able to bypass the blocking activity of methotrexate to prevent sys­temic toxicity. It can also be given locally as a mouthwash or as eye drops.

Methotrexate is well absorbed orally at low doses, but higher doses are given parenterally. An initial fast half-life is followed by a prolonged phase of renal excretion and a long terminal half-life. This is responsible for methotrexate toxicity to the bone marrow, mucous membranes and gastrointestinal tract - areas of high cell turnover and active DNA synthesis. Because methotrexate can accumu­late in third spaces and be slowly released into the circulation, its use should be avoided in patients with effusions because of the risk of severe toxicity. Methotrexate also penetrates the blood-brain barrier at high doses, and can be given intrathecally for meningeal disease. With high doses, adequate diuresis should be obtained. It is also 50 per cent albumin bound and can be displaced by other protein-bound drugs, leading to higher systemic levels of free methotrexate and increased toxicity. However, it is generally well tolerated, with few side effects unless the risk factors are not taken into account. Severe toxicity is manifested by myelosup-pression, oropharyngeal ulceration and diarrhoea, with renal and hepatic failure and pneumonitis seen less commonly. Indications for use are as part of combination regimens in breast cancer, haematological malignancies, osteosarcoma and choriocarcinoma.

Methotrexate is also known to act partly through inhib­ition of TS, which catalyses the methylation of deoxyuridy-late (dUMP) to thymidylate, which is then incorporated into DNA. More specific inhibitors of TS have been devel­oped, which target the folate-binding site of the enzyme. Raltitrexed (Tomudex) acts as a direct and specific TS inhibitor which, once transported into cells, is extensively polyglutamated to chemical entities that are even more potent inhibitors of TS. Such polyglutamation increases the duration of TS inhibition, which in theory could improve anti-tumour activity. Pemetrexed targets TS, but also inhibits dihydrofolate reductase and glycinamide ribonucleotide formyl transferase (GARFT), folate-dependent enzymes involved in purine synthesis. Again, once inside the cell, pemetrexed is an excellent substrate for folylpolyglutamate synthase.

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