Chemotherapy and related treatments

Published on 03/04/2015 by admin

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Last modified 03/04/2015

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Chemotherapy and related treatments

General principles

The life cycle of the normal cell is shown schematically in Figure 27.1. Conventional anti-leukaemic and lymphoma cytotoxic drugs can be broadly divided into those agents active during only one phase of the cell cycle (‘phase-specific’) and those acting at all stages (‘phase non-specific’). In practice, most anti-leukaemic drugs act predominantly against proliferating cells and therefore affect a fraction of the malignant cell population. Thus, if in advanced acute leukaemia the total number of malignant cells is 10¹⁰, a single course of chemotherapy could be expected to kill between 2 and 5 log of cells, leaving between 10⁵ and 10⁸ residual leukaemic cells. It can be seen that the chance of eradication of the disease by chemotherapy is favoured by early treatment when the leukaemic mass is small and by repeated courses of cytotoxic drugs. It is also logical to combine different agents to maximise the anti-leukaemic activity and exploit different toxicities (‘combination chemotherapy’).

Fig 27.1 The cell cycle.

Major classes of conventional cytotoxic drugs

Alkylating agents

Despite their variable structure, all alkylating agents appear to have a common mechanism with cross-linking of DNA the principal cytotoxic action. Agents commonly used in haematological practice include melphalan, chlorambucil, cyclophosphamide, busulfan and bendamustine. These are toxic to rapidly proliferating cells and the dose-limiting toxicity is myelosuppression. Other side-effects include infertility, haemorrhagic cystitis (cyclophosphamide) and an increased risk of secondary malignancy.

Antimetabolites

These drugs are compounds which interfere with the utilisation of a natural metabolite by virtue of the similarity of their chemical structure. Most are analogues of nucleic acid precursors. Commonly used examples are the folinic acid analogue methotrexate, the purine analogues 6-mercaptopurine and fludarabine, and the pyrimidine analogue cytosine arabinoside. The alkylating agent bendamustine also has some antimetabolic activity. The main toxic effect of the group is myelosuppression. Fludarabine is significantly immunosuppressive.

Topoisomerase poisons and inhibitors

This broad class of drugs includes the anthracyclines (doxorubicin, daunorubicin, mitoxantrone, idarubicin) and the epipodophyllotoxins (etoposide). The anthracyclines are cell cycle non-specific drugs. The acute dose-limiting toxicity is bone marrow suppression but the cumulative dosage is limited by cardiotoxicity. Etoposide is a phase-specific drug (active in G₂) with myelosuppression the major toxicity.

Spindle poisons

Key agents in this group are the two vinca alkaloids, vincristine and vinblastine. They are cell-cycle phase-specific, exerting a cytotoxic effect by binding to cellular microtubular protein and inhibiting mitosis. Vincristine’s major adverse effects are mixed motor-sensory and autonomic neuropathies (patients usually initially complain of ‘pins and needles’ in the fingers or toes and constipation); vinblastine is less neurotoxic but causes more bone marrow suppression.

Side-effects of conventional cytotoxic drugs

Some toxic effects are common to many cytotoxic drugs and must be discussed with all patients receiving a relevant single agent or combination chemotherapy (Table 27.1

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