ANTHRACYCLINES
Doxorubicin hydrochloride is one of the most widely used anti-cancer drugs and has the broadest spectrum of activity of all chemotherapeutic agents. Daunorubicin was first isolated from Streptomyces in the 1960s, and was found to have activity against a variety of cancers. Mutations of Streptomyces led to a new strain from which doxorubicin was isolated. These two first-generation anthracyclines differ structurally by a single hydroxyl group, which results in a considerable difference in their anti-tumour activity. The mechanism of action has not been completely determined, but seems to involve DNA intercalation, free-radical formation, covalent DNA binding and inhibition of the enzyme topoisomerase II.
Daunorubicin is mainly used for the treatment of acute non-lymphocytic leukaemia, whereas doxorubicin has a much wider spectrum of activity and is particularly used in the treatment of lymphomas, small-cell lung cancer, breast cancer, upper gastrointestinal cancer, sarcomas and ovarian cancer. Doxorubicin is administered by the intravenous route and is rapidly metabolized by the liver, to be excreted in bile. Caution must be used in hepatic dysfunction, and it (and all anthracyclines) is highly vesicant. Other toxicities include emesis, myelosuppression, oropharyn-geal ulceration, diarrhoea and alopecia. The major long-term complication is a cumulative, dose-limiting cardiotoxicity, which is irreversible and may be fatal. Doses are usually up to 75 mg/m2 as a single agent every 3 weeks, but cardiotoxicity becomes increasingly frequent at cumulative doses of 450 mg/m2. ‘Cardioprotectors’ such as bisdioxopiper-azine have been developed in an attempt to circumvent this cardiotoxicity, and are thought to work by chelating iron required by doxorubicin to produce the free radicals proposed to initiate the membrane damage evident in cardiac cells.
Developmental chemistry has produced more than 1000 structural anthracycline analogues in an attempt either to increase activity of the drug or decrease toxicity, especially cardiac. Most do not proceed to clinical testing, and many get to trials only to demonstrate no clear advantage over doxoru-bicin or different toxicities. Epirubicin was synthesized in 1975 and has a similar spectrum of activity to doxorubicin while exhibiting less chronic cardiotoxicity. Idarubicin was shown to have a high affinity for lipids, and therefore can be administered effectively by the oral route.
Liposomal drug-delivery systems (e.g. daunorubicin encapsulated by distearoylphosphatidylcholine/cholesterol, DaunoXome, and polyethylene glycol (PEG)-coated liposomal encapsulation of doxorubicin, Caelyx) have been extensively investigated as carriers for anti-cancer agents. Both DaunoXome and Caelyx have longer half-lives, higher AUCs and lower clearances than either free daunorubicin or doxorubicin, and also appear to be free of significant cardiotoxicity, and generally have decreased anthracycline-like toxicities. However, myelosuppression is still an important feature of both formulations at recommended doses, with neutropenia occurring at grade III/IV in 50-60 per cent of patients. In addition, plantar-palmar erythrodysaesthesia was noted to be dose limiting at higher cumulative doses of Caelyx. Liposomal drug-delivery systems have been found to be especially useful in the treatment of autoimmune deficiency syndrome-associated Kaposi’s sarcoma (AIDS-KS), as conventional treatment with anthracyclines tends to be limited by cumulative toxicities (especially cardiac) preventing prolonged courses of chemotherapy.
MITOXANTRONE
Mitoxantrone is based on the anthracenedione structure. It is completely synthetic and was designed with the aim of retaining anthracycline anti-tumour activity with less tox-icity. It undergoes DNA intercalation, in a similar fashion, and also inhibits topoisomerase II. It is given by intravenous injection and has a long terminal half-life of up to 40 hours. It is used in leukaemia, breast cancer and in combination regimens for the treatment of lymphomas. The reduced toxicity profile makes it an attractive drug to use in the elderly breast cancer patient. In addition, cardiac toxicity is less than that due to doxorubicin, probably as a result of its decreased free-radical production.
BLEOMYCIN
Bleomycin is a mixture of low-molecular-weight glycopep-tides isolated from the fungus Streptomyces verticullus and has both anti-bacterial and anti-cancer activity. The mechanism of cytotoxicity appears to relate to DNA binding and the production of strand breakage, with ferrous iron being essential to this mechanism. It is administered by parenteral injection and is renally excreted, with an initial half-life of 30 minutes and a later elimination phase of 2-9 hours. It is generally administered either by intravenous infusion or intramuscular injection, and also has utility via the intra-cav-ity route to control pleural or pericardial effusions. It has virtually no myelosuppressive toxicity or gastrointestinal side effects. Chronic administration can produce pneumonitis, which can lead to an irreversible and occasionally fatal interstitial fibrosis. Fevers, chills and flu-like symptoms are common, and prolonged administration also leads to skin pigmentation. It is used mainly in combination regimens for the treatment of germ-cell tumours and lymphomas.
ACTINOMYCIN D
This compound is also isolated from Streptomyces and acts in a similar fashion, by DNA intercalation and the induction of strand breaks. It is eliminated almost unchanged in the bile and urine. Actinomycin D is usually administered intravenously. It is active against choriocarcinoma, Wilms’ tumour, Ewing’s sarcoma, embryonal rhabdomyosarcoma and, to a lesser extent, testicular cancer, lymphoma and Kaposi’s sarcoma. The main toxicities are myelosuppres-sion, mucositis, diarrhoea and alopecia. In addition, drug extravasation can lead to severe tissue necrosis. Actinomycin D appears to inhibit DNA repair after radiation damage, and therefore the combination of both modalities enhances the risk of toxicity.
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