Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeut ics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular his tology in a tumour model did not closely correlate with activity in the sam e human cancer histology, casting doubt on the correspondence of the pre-cl inical models to clinical results. However, for compounds with in vivo acti vity in at least one-third of tested xenograft models, there was correlatio n with ultimate activity in at least some Phase II trials. Thus. an efficie nt means of predicting activity in vivo models remains desirable for compou nds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models . the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre ac tivity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P < 0.0001). Intraperitonea l hollow fibre activity was also found to be a better predictor of xenograf t activity than either subcutaneous hollow fibre activity or intraperitonea l plus subcutaneous activity combined. Since hollow fibre activity was a us eful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell li ne in vitro cancer drug screen and hollow fibre assay. A positive correlati on was found for histologic selectivity between in vitro and hollow fibre r esponses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growt h inhibition below 10(-75) M were active in more than 6 intraperitoneal fib res whereas only 4% of compounds with a potency of 10(-4) M achieved the sa me level of hollow fibre activity (P < 0.0001). Structural parameters of th e drugs analysed included compound molecular weight and hydrogen-bonding fa ctors, both of which were found to be predictive of hollow fibre activity. (C) 2001 Cancer Research Campaign.