Earlier approaches to drug discovery

The main approach used over the past 50 years has been to screen libraries of compounds (both chemically synthesized and natural products) either for cytotoxic activity against tumour cells in cell culture or for anti-cancer activity in tumour-bearing animals (e.g. inhibition of tumour growth or increase in life span of the host). This has been successful in that it has led to the discovery and clinical use of many of the major classes of established anti-cancer drugs e.g. alkylat-ing agents, anthracyclines, topoisomerase inhibitors, and microtubule binders.

Historical developments in screening are best illustrated by the evolution of methodologies used by the influential National Cancer Institute in the US. In the early days, screening was commonly carried out against a mouse leukaemia, either the P338 or L1210 models. But success in identifying drugs with activity in leukaemias and lympho-proliferative malignancies did not translate well to the major solid tumours. Hence, in the mid-1970s, transplantable mouse solid tumours, and then human tumour xenografts, were included as a secondary panel. A decade later the need for an even greater focus on human cancer led to the introduction of a 60-cell line in vivo tumour panel as the primary screen. Promising activities arising from this were followed up in animal studies.

In some cases, the compound discovered in the screen was developed through preclinical and clinical testing. In others, a range of chemical analogues of the parent compound, already available or newly synthesized, were evaluated for improved performance.

These earlier approaches were very pragmatic. Studies of mode of action were commonly only conducted late in the development of a cytotoxic. Exceptions to this were the antimetabolite and antihormonal approaches. In these cases, compounds were usually designed rationally to inhibit a target enzyme (e.g. dihydrofolate reductase, thymidylate synthetase, aromatase) or to antagonize a receptor (e.g. for oestrogen or androgen). Thus, the primary screen was frequently for the biochemical mode of action, and studies to check for compliance with the desired mechanism could be included in subsequent in vitro and in vivo tests (e.g. thymidine reversal for thymidylate synthetase, oestrogen levels for aromatase).

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