PREDNISOLONE RESISTANCE IN CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA - VITRO-VIVO CORRELATIONS AND CROSS-RESISTANCE TO OTHER DRUGS

As an important determinant of response to chemotherapy, accurate meas urement of cellular drug resistance may provide clinically relevant in formation. Our objectives in this study were to determine the relation ship between in vitro resistance to prednisolone (PRD) measured with t he colorimetric methyl-thiazol-tetrazolium (MTT) assay, and (1) short- term clinical response to systemic PRD monotherapy, (2) long-term clin ical outcome after combination chemotherapy within all patients and wi thin the subgroups of clinical good and poor responders to PRD, and (3 ) in vitro resistance to 12 other drugs in 166 children with newly dia gnosed acute lymphoblastic leukemia (ALL). The 12 clinical poor PRD re sponders had ALL cells that were median 88-fold more in vitro resistan t to PRD than 131 good responders (P = .013). Within all patients, inc reased in vitro resistance to PRD predicted a significantly worse long -term clinical outcome, at analyses with and without stratification fo r clinical PRD response, and at multivariate analysis (P less than or equal to .001). Within both the clinical good and poor responder subgr oups, increased in vitro resistance to PRD was associated with a worse outcome, which was significant within the group of clinical good resp onders (P < .001). LC50 values, ie, lethal concentrations to 50% of AL L cells, for PRD and each other drug correlated significantly with tho se of all other 12 drugs, with an average correlation coefficient of 0 .44 (standard deviation 0.05). The highest correlations were found be tween structurally related drugs. In conclusion, in vitro resistance t o PRD was significantly related to the short-term and long term clinic al response to chemotherapy, the latter also within the subgroup of cl inical good responders to PRD. There was a more general in vitro cross -resistance between anticancer drugs in childhood ALL, although drug-s pecific activities were recognized. (C) 1998 by The American Society o f Hematology.