Making the most of rodent tumour systems in cancer drug discovery

– 11.7 1.2 × 104 40 It is clear that even after almost half a century of intensive effo develop effective treatments for common solid cancers the still some way to go before a major impact on survival of pati with these malignancies is achieved. Much of the paucit success is blamed on the lack of appropriate models and the commonly held belief amongst cancer researchers that t plantable tumours in rodents are sensitive to drug therapy, are to cure and therefore not predictive of responses in humans true that, in the past, when one considers the large numb compounds evaluated, murine tumour models have identified a limited number of clinically useful agents and not a sin cancer-specific drug has resulted from a murine tumour scre is easy with hindsight to blame this disappointing lack of re effective therapies on inappropriate test systems and scre strategies but, although drug discovery from rodent system been sparse, in reality, an enormous contribution to cancer th principles has emanated from such studies. This work really b in the mid 1950s when the National Cancer Institute (NCI) in USA initiated a large-scale anti-cancer drug-screening progra using three murine tumour models: sarcoma 180, L1 leukaemia and carcinoma 755 (Plowman et al, 1997). Of m significance in the early days was the work of Skipper colleagues who, by the use of experimental leukaemia mo established the principle of survival/inoculum relations (Skipper et al, 1957) and also the concept of fractional cell kill that the percentage of the tumour cell population killed by a g dose of drug was relatively constant (Skipper et al, 1964). also described a close relationship between dose leve percentage of leukaemic cell population killed, i.e. dose–response relationship. Other useful therapeutic stra were first established in rodent systems. The principle of optim scheduling was first described by Goldin et al (1956) using L1210 leukaemia. Combination chemotherapy and the conce therapeutic synergism was first investigated in rodent mo (Goldin and Mantel, 1957) as was combining the modalitie surgery and chemotherapy – adjuvant chemotherapy (M 1981). Many of the early experimental studies utilized mur leukaemias which grew very rapidly, had a high growth frac and proved to be sensitive to a number of agents that were s quently shown to have more activity against leukaemias lymphomas than against solid carcinomas or sarcomas and toxic to the bone marrow (Muggia, 1987). A number of invest