ANTICANCER AGENTS

2010

ANTICANCER AGENTS are commonly referred to as antineoplastic agents, however, by strict definition, antineoplastic agents are used to treat a neoplasm’ (meaning a ‘new growth’). Neoplasms that have only the characteristic of localized growth are classified as benign. Neoplasms with the additional characteristic of invasiveness, and/or the capacity to metastasise, are classified as malignant. The term cancer’ is usually applied only to the latter group. Similarly, the word tumour (meaning literally ‘a local swelling’) tends to be used in association with cancer, and antineoplastic agent’ is commonly interchangeable with ‘anticancer’.

There are a number of approaches to the chemotherapy of cancer, and most can be regarded as complementary or additional to radiotherapy and surgery. Direct approaches to cancer mostly use cytotoxic agents: these work by interfering with cell replication or production, so preventing the growth of new cancerous tissue. Inevitably, this means that normal cell production is also affected, causing serious side-effects. There are many cytotoxic agents with diverse modes of action, but these can be divided into groups on the basis of their mechanisms of action.

Alkylating agents and related compounds act by forming covalent bonds with DNA, thus impeding DNA replication. They can be divided into five subgroups: (i) nitrogen mustards (e.g. chlorambucil, cyclophosphamide. melphalan and mustine; (ii) platinum drugs (coordination complexes of platinum) (e.g. cisplatin and carboplatin); (iii) nitrosoureas (e.g. carmustine. lomustine, semustine andstreptozocin); (iv) busulfan-like agents; (v) other alkylating agents, e.g. ethoglucid, tbiotepa and treosulfan.

Antimetabolites block or subvert pathways in DNA synthesis in various ways, and can be divided as follows: (i) folate antagonists (e.g. methotrexate): (ii) pyrimidine analogues: fluorouracil and cytarabine (cytosine arabinoside); (iii) purine analogues (e.g. mercaptopurine, thioguanine and pentostatin). Some other purines are used for non-malignant conditions, e.g. azathioprine and allopurinol Also some of these agents (e.g. methotrexate) act through being DIHYDROFOLATE REDUCTASE INHIBITORS.

Cytotoxic antibiotics produce their effect mainly by direct action on DNA. Anthracyclines include the important drugs doxorubicin, aclarubicin and idarubicin. Related compounds are mitozantrone and epirubicin. Some others are the Streptomyces antibiotic dactinomycin, and the metal-chelating glycopeptides especially bleomycins. Mitomycin effectively is a prodrug that is converted in the body to an alkylating agent.

Plant derivatives are from several sources. Vinca alkaloids, including vincristine, vinblastine and vindesine, are from the periwinkle Vinca rosea, and act by binding to tubulin. Etoposide is a derivative from mandrake root (Podophyllum peltatum), which may work by inhibiting mitochondrial function. Paclitaxel and related ‘taxane’ compounds, such as docetaxel, are developed from a compound in Western yew (Taxus brevifolia) tree bark, and work by interfering with microtubule function.

Miscellaneous agents. Crisantaspase is a preparation of the enzyme asparaginase, which breaks down asparagine to aspartic acid and ammonia. When crisantaspase is given intravenously, it is toxic in tumour cells that have lost the capacity to synthesize asparagine (e.g. in acute lymphoblastic leukaemia cells). Hydroxyurea is a urea analogue that interferes with ribonucleotide reductase catalysed conversions. Amsacrine acts similarly to doxorubicin. Mitotane interferes with the synthesis of adrenocortico-steroids, having an eventual cytotoxic action on the adrenal cortex, and so can be used for tumours of these cells.

Indirectly acting anticancer agents are not cytotoxic, though their use can be very effective, and often less toxic than direct approaches, CORTICOSTEROIDS (e.g. prednisone) are also used in the treatment of the lymphatic cancer Hodgkin’s disease and other forms of lymphoma, and may be helpful additionally in halting the progress of hormone-linked breast cancer. In cases where the growth of a tumour is linked to the presence of a sex hormone (as with some cases of breast cancer or cancer of the prostate gland) treatment with sex hormones opposite to the patient’s own can be extremely beneficial. Examples are oestrogens, such as fosfestrol, which can be used to block the effects of androgens in androgen-dependent prostatic tumours. Progestogens such as megestrol and medroxyprogesterone have been used in endometrial neoplasms and hypernephromas. The antioestrogen tamoxifen has extensive use in treating hormone-dependent breast cancers, and may also have a role in preventing them. Some agents act indirectly to alter sex hormone production, and these include analogues of gonadotrophin-releasing hormone (e.g. goserelin), or the antiandrogen cyproterone. Also, octreotide, a somatostatin analogue, can be used for the relief of symptoms originating from the release of hormones from carcinoid tumours of the endocrine system, including VIPomas and glucagonomas (see SOMATOSTATIN RECEPTOR AGONISTS). Radiopharmaceutical agents deliver toxic radioisotopes to their sites of action, e.g. I in treating thyrotoxicosis. There are a number of other approaches to the treatment of cancer, especially involving molecular biology techniques such as antisense oligonucleotides, vaccination approaches, and also the use of immune reaction modifiers. See ANTIANDROGENS; AROMATASE INHIBITORS; IMMUNOMODULATORS; OESTROGENS; 5α-REDUCTASE INHIBITORS.