P450 enzyme expression patterns in the NCI human tumor cell line panel

Cytochrome P450 (P450) enzyme expression patterns were determined for a pan el of 60 human tumor cell lines, representing nine tumor tissue types, used by the National Cancer Institute (NCI) Anticancer Drug Screening Program. All 60 tumor cell lines displayed significant P450 activity, as well as P45 0 reductase activity, as determined using the general P450 substrate 7-benz yloxyresorufin. Cell line-specific P450 enzyme patterns were observed using three other P450 substrates, 7-ethoxycoumarin, coumarin, and 7-ethoxyresor ufin, each of which was metabolized at a low rate. Using a pattern-matching computer program, COMPARE, correlative relationships were investigated bet ween the arrays of P450 activities and the patterns of cytotoxicity exhibit ed by a large group of anticancer agents of proven or potential clinical ut ility. Significant negative correlations between the patterns of P450-depen dent 7-benzyloxyresorufin metabolism activity and cell line chemosensitivit y were observed for 10 standard anticancer agents (including 6 alkylating a gents) and 55 investigational compounds, suggesting a role for P450 metabol ism in the inactivation of these agents. Negative correlations between 7-et hoxycoumarin O-deethylation and cell line chemosensitivity to a group of to poisomerase inhibitors were also seen, again suggesting P450-dependent drug inactivation. P450 enzyme profiling may thus aid in interpreting the patte rns of drug sensitivity and resistance in the NCI tumor cell panel, and may facilitate the identification of anticancer agents whose activity can be a ltered via cytochrome P450 metabolism.