Rationale for cytotoxic chemotherapy

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Cytotoxic chemotherapy began with sulphur mustards (oily vesicant liquids) which had been developed and used as chemical weapons in World War I (1914-18). Amongst their actions depression of haemopoiesis and of lymphoid tissues were observed. Preparations for World War II (1939^5) included research to increase the potency and toxicity ('efficacy') of these odious substances. Substitution of a nitrogen atom for the sulphur atom, i.e. making nitrogen mustards, had the desired result. The disappearance of lymphocytes and granulocytes from the blood of rabbits was a useful marker of toxicity and gave rise to the idea of possible efficacy in lymphoid cancers.

The problem was fundamental and simple: could one destroy a tumour with this group of cytotoxic agents before destroying the host?2

Nitrogen mustards, as anticancer alkylating agents, were first tested on experimental lymphoma in mice and the results were sufficiently encouraging to warrant a therapeutic trial in man. 'The response of the first patient was as dramatic as that of the first mouse', following 10 days treatment. But severe bone marrow damage occurred and, disappointingly, as the bone marrow recovered so did the tumour; in addition, with further courses, the tumour rapidly became resistant.

Twenty years later (1963) we can appreciate how accurately this first patient reflected the future trials and tribulations of therapy with alkylating agents.2

Other classes of cytotoxic agents, e.g. anti-metabolities, were subsequently identified and used to treat cancer patients. Their efficacy evidently was limited by their relative nonselectivity for proliferating cells: the narrow therapeutic index of cytotoxic agents means that escalation of drug doses is constrained by damage to normal cells and maximum doses which can be safely administered to patients are often suboptimal to achieve total

2 Gilman A 1963 American Journal of Surgery 105: 574.

cancer cell killing. Even so, cytotoxic chemotherapy agents remain the mainstay of systemic anticancer treatment, since an understanding of their pharmacology has enabled clinicians to exploit the benefits of these drugs by various means (see below).

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