24.03.2 Cytotoxic Antibiotics

Several antibiotics are widely used as anticancer drugs. They include a group of anticancer drugs known as the anthracycline antibiotics, typified by daunorubicin and its close structural compound doxorubicin, both isolated from Streptomyces. They owe their cytotoxic action principally to their ability to interact with DNA (intercalation) leading to a disruption of DNA function. The drugs insert non-specifically between adjacent base pairs in the DNA and bind to the phosphate-sugar backbone promoting local uncoiling and blocking DNA and RNA synthesis. In addition, these compounds are also able to inhibit the topoisomerase enzymes causing irreparable breaks in supercoiled DNA, further inhibiting DNA and RNA synthesis. Furthermore, oxygen free radical production by these agents also plays a major role in their cytotoxicity, although chronic administration can lead to cardiotoxicity because the heart lacks the catalase enzyme required to inactivate the oxygen free radicals.

Daunorubicin is used in the treatment of acute myeloblastic and acute lymphoblastic leukaemias, whilst doxorubicin, which is one of the most important and widely used anticancer drugs, is indicated for a number of cancers including breast and lung carcinomas and acute lymphoblastic leukaemia. Both drugs cause irreversible, dose dependent cardiotoxicity which is regarded as the major adverse effect associated with them although transient bone marrow suppression, stomatitis, vomiting and alopecia can also occur.

Another antibiotic used as a cancer therapeutic is dactinomycin which is isolated from soil bacteria of the genus Streptomyces. Similarly to daunorubicin and doxorubicin, dactinomycin intercalates into the minor groove of DNA forming a stable complex which interferes with RNA polymerase and inhibiting transcription. It is used in the treatment of Wilms’ tumour and gestational choriocarcinoma (cancer of the placenta). The major adverse effective is bone marrow suppression, thus the drug is immunosuppressive. In addition, common adverse effects such as nausea, vomiting, diarrhoea, stomatitis and alopecia have been noted.

A final anticancer antibiotic is another Streptomyces-derived compound, bleomycin. This drug, unlike the other antibiotics described above, is cell-cycle specific and mediates its effects by causing superoxide-mediated single and double stranded breaks in DNA which results in a reduction in DNA synthesis and subsequent inhibition of cell division and growth. Bleomycin is used primarily in the treatment of testicular cancers, as part of a cocktail of other anticancer drugs including cisplatin and vinblastine.  It is also effective, although not curative, for squamous cell carcinomas.