24.02.2 The Principles of Anticancer Chemotherapy

The aim of drug treatment in patients with cancer is to eradicate the presence of malignant cells or, if this is not possible, provide effective palliation to lessen the severity of the symptoms. This may be achieved by causing a lethal cytotoxic event in the cancer cell that will arrest tumour progression. Targets for cytotoxic attack include inhibition of purine and pyrimidine synthesis, inhibition of DNA and RNA synthesis and chemical attack on the integrity of the structure of cellular DNA. Since these treatments inhibit the mechanisms of cell proliferation in general, they are toxic to both tumour cells and normal, non-cancerous proliferating cells. Thus selectivity of cytotoxic drugs has traditionally relied on the fact that in tumour tissue there is a higher proportion of cells undergoing division and proliferation that are susceptible to the effects of the drugs when compared to normal tissue. Proliferating cells in the bone marrow, gastrointestinal tract and hair follicles are particularly sensitive to many of these cytotoxic agents resulting in many of the adverse effects associated with these drugs (leukopaenia/low/loss of white blood cells, thrombocytopaenia/low/loss of platelets, nausea, vomiting, alopecia/hair loss).

However there are a number of problems associated with the use of drugs in chemotherapy. These include cytotoxicity, drug resistance and induction of new tumours. As mentioned above, by their very nature many anticancer drugs will target and kill normal cells as well as tumour cells, thus contributing to the common toxic manifestations of chemotherapy such as vomiting, alopecia and diarrhoea. Although these are generally transient side-effects and symptoms can be alleviated by the use of concomitant drug therapies such as anti-emetics, some more serious, irreversible adverse effects such as myelosuppression (i.e suppression of bone marrow leading to reduced synthesis of blood cells) and cardiac, bladder and pulmonary toxicities can occur.

Another common problem associated with the use of anticancer drugs is resistance of the tumour cells to the drug. Some cancers such as melanoma are inherently resistant to treatment whilst others tumour types may acquire resistance. Design of drug regimens that utilise short term, intensive intermittent therapy with combinations of drugs are effective in minimising drug resistance in most cases. Finally, since most anticancer drugs are mutagens, there is a danger of new cancers (neoplasms) arising following treatment. For example, occurrence of acute non-lymphoblastic leukaemia some ten years after treatment to cure an original tumour has been observed. This is a particular problem with use of the alkylating agent class of anticancer drugs.