Cytotoxic chemotherapy drugs exert their effect by inhibiting cell proliferation. All proliferating cells, whether normal and malignant, cycle through a series of phases of: synthesis of DNA (S phase) mitosis (M phase) and rest (G; phase). Noncycling cells are quiescent in G0 phase (Fig. 30.1). Cytotoxic drugs interfere with cell division at various points of the cell cycle, e.g. synthesis of nucleotides from purines and pyrimidines, of DNA and RNA, and interference with mitosis. They are potentially mutagenic. Such drugs ultimately induce cell death by the process of apoptosis.3'4 This is a process by which single cells are removed from the midst of living tissue by fragmentation into membrane-bound particles and phagocytosed by other cells, without disturbing its architecture or function, or eliciting an inflammatory response. The instructions for the response are built into the cell's genetic material, i.e. 'programmed cell death'.5
In general cytotoxics are most effective against actively cycling cells and least effective against resting or quiescent cells. The latter are particularly problematic in that, although inactive, they retain the capacity to proliferate and may start cycling again after a completed course of chemotherapy, often leading to rapid regrowth of the cancer at a later date. Cytotoxic drugs can be classified as either:
• Cell cycle nonspecific: these kill cells whether resting or actively cycling (as in a low growth
3 Greek: apo, off; ptosis, a falling
4 Bellamy C O et al 1995 Cell death in health and disease: the biology and regulation of apoptosis. Seminars in Cancer Biology 6 (1): 3-16.
5 Dysregulated apoptosis is also involved in the pathogenesis of many forms of neoplastic disease, notably many lymphomas; understanding its mechanisms and the defective processes offers scope for novel approaches to the treatment of cancer.
^commits cell V to divldel
S ¡DNA replication]
Alkylating agents Antimetabolites Cytotoxic antibiotics Platinum drugs Topolsomerase inhibitors
Most cytotoxic chemotherapy drugs inhibit the processes of DNA replication or mitosis Fig. 30.1 The cell cycle fraction cancer such as solid tumours, e.g. alkylating agents, doxorubicin and allied anthracyclines) • Cell cycle (phase) specific: these kill only cells that are actively cycling (often because their site of action is confined to one phase of the cell cycle, e.g. antimetabolite drugs).
A list of drugs currently in clinical use appears in Table 30.2.
Table 30.3 provides detail of toxicity of individual agents. The following is an overview of the mode of action and toxicity and use of the principal groups of cytotoxic drugs.
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