The ability to give anticancer treatment via the bloodstream was a major advance as it enabled therapy to potentially reach metastatic disease in any part of the body. The toxicity of chemotherapy determined that drugs could only be given intermittently and that time had to be allowed for normal tissues to recover between each administration of new cytotoxic drugs. Furthermore, it quickly became apparent in the early development of cytotoxic chemotherapy that tumours rapidly developed resistance to single agents given on their own. For this reason the principle of intermittent combination chemotherapy was developed. Several drugs were combined together, chosen on the basis of differing mechanisms of action and non-overlapping toxicities. These drugs were given over a period of a few days followed by a rest of a few weeks, during which time the normal tissues had the opportunity to recuperate. Although the tumour cells also had the same opportunity for regrowth, it became apparent that normal tissues repaired more rapidly than cancer cells and it was therefore possible to continually deplete the tumour while allowing the restoration of normal tissues between chemotherapy cycles. In many experimental tumours it has been shown that there is a log linear relationship between drug dose and number of cancer cells killed. With a chemosensitive tumour a relatively small increase in dose may have a large effect on tumour cell kill. It is therefore apparent that where cure is a realistic option the dose administered may be critical and may need to be maintained despite toxicity. In situations where cure is not a realistic possibility and palliation is the aim, dose is less critical particularly as quality of life becomes paramount.
Classification of cytotoxic drugs
The alkylating agents were first developed for use in chemical warfare. They act by covalently bonding alkyl groups and their major effect is to cross-link DNA strands, interfering with DNA synthesis. Despite being among the earliest cytotoxic drugs developed they maintain a central position in the treatment of cancer in the 1990s. Common alkylating agents include cyclophosphamide, chlorambucil, melphalan and busulphan.
Antimetabolites are usually structural analogues of naturally occurring metabolites and interfere with normal synthesis of nucleic acids by falsely substituting purines and pyrimidines in metabolic pathways. Antimetabolites can be divided into folic acid antagonists, pyrimidine antagonists and purine antagonists. The classic folic acid antagonist methotrexate is structurally very similar to folic acid and binds preferentially to dihydrofolate reductase, the enzyme responsible for the conversion of folic acid to folinic acid. It is widely used in the treatment of solid tumours and haematological malignancies and also has a role in non-malignant conditions such as rheumatoid arthritis.
The two major pyrimidine antagonists are 5-fluorouracil and cytosine arabinoside (cytarabine). 5-Fluorouracil consists of a uracil molecule with a substituted fluorine atom. It acts by blocking the enzyme thymidylate synthetase which is essential for pyrimidine synthesis. 5-Fluorouracil has a major role in the treatment of solid tumours, particularly gastrointestinal cancers. Cytosine arabinoside is used almost exclusively in the treatment of acute myeloid leukaemia where it remains the backbone of therapy.
6-Mercaptopurine and 6-thioguanine are purine antagonists which are both used almost exclusively in the treatment of acute leukaemia.
These are isolated from the periwinkle plant and the major drugs in this class are vincristine and vinblastine. They act by binding to tubulin and inhibiting microtubule formation and have a role in the treatment of haematological and non-haematological cancers. They are perhaps best known for their potential for causing neurotoxicity.
These are semi-synthetic derivatives of podophyllotoxin which is an extract from the mandrake plant. Etoposide is a drug used in a wide range of cancers and works by producing DNA strand breaks by acting on the enzyme topoisomerase II.
Taxol is a new anticancer drug isolated from the bark of the Western Yew. This drug also acts by inhibiting tubulin. It has already demonstrated a high level of activity inovarian and breast cancer and may have a large role to play in the treatment of cancer in the future.
These drugs act by intercalating adjoining nucleotide pairs on the same strand of DNA. They include doxorubicin, daunorubicin, mitozantrone, mitomycin C and bleomycin. These drugs have a wide spectrum of activity in haematological and solid turnours. Doxorubicin is one of the most widely used of all cytotoxic drugs.
Cisplatin and carboplatin cause interstrand cross-links of DNA and are often regarded as non-classical alkylating agents. They have transformed the treatment of testicular cancer and have a major role to play in many other tumours including ovarian cancer and head and neck cancar. Side-effects of chemotherapeutic drugs.
The side-effects of anticancer drugs are legendary and have created fear in both the medical profession and the general public. The situation in the 1990s has improved vastly from the early days of cytotoxic chemotherapy where persistent and prolonged nausea and vomiting were the rule, and life-threatening complications from myelosuppression were not uncommon. Modern cytotoxic chemotherapy has improved out of all recognition to those early days and newer cytotoxic drugs, often analogues of the original drugs, are frequently associated with significantly lesser side-effects. Modern antiemetics such as the 5 hydroxy tryptamine (5HT3) antagonists can prevent or reduce vomiting to a minimum in a majority of patients. In those intensive chemotherapy regimens where myelosuppression is a major feature, the use of growth factors can now reduce this to a certain extent. Despite these advances, chemotherapy still carries many potentially serious side-effects and should only be used by practitioners with considerable skill and experience.
Nausea and vomiting
This common side-effect can be eliminated or reduced by choice of drugs and by using modern antiemetics. Nausea and vomiting are particular problems with platinum analogues and with doxorubicin. Antiemetics such as metoclopramide and domperidone are used initially but the 5HT3 serotonin antagonists (ondansetron and granisetron) have revolutionized management of vomiting and many patients are now given platinum drugs as an outpatient.
Many but not all cytotoxic drugs are capable of causing hair loss. Scalp cooling can sometimes be used to reduce hair loss with doxorubicin but in general this side-effect can only be prevented by selection of drugs where this is possible. Hair always regrows on completion of chemotherapy.