CELLULAR-DRUG RESISTANCE IN CHILDHOOD LEUKEMIA

The response to chemotherapy is determined essentially by two factors: first, pharmacokinetic factors, determining which concentration of dr ug reaches the malignant cells, and second, cellular drug resistance o f these cells, determining how many of them will be killed by that con centration of drug. The study of cellular drug resistance has been sti mulated by the development of short-term 'total cell kill' assays, suc h as the MTT assay, for use on patient samples. The drug resistance pr ofiles differed markedly between ALL and ANLL, between immunophenotypi c and karyotypic subgroups within ALL, and between initial and relapse d ALL. The results of the MTT assay showed a significant relation betw een the antileukemic activity of prednisolone in vitro and the clinica l response to systemic monotherapy with that drug. At multivariate ana lysis including several well-known prognostic factors (WBC, age, immun ophenotype) only the in vitro resistance to prednisolone, dexamethason e, L-asparaginase, and daunorubicin was significantly related to clini cal outcome. At multiple regression analysis, combination of the resul ts for prednisolone, L-asparaginase, and vincristine made it possible to distinguish between three patient groups with increasing levels of drug resistance and markedly different probabilities of 2-year disease -free survival: 100%, 83%, and 60%. These results show that in vitro d rug resistance testing can give a correct prediction of prognosis, sup erior to that of currently used prognostic factors. Stratification of prognostic groups based on the results of drug resistance testing is f easible and should be introduced into new clinical trials. Many questi ons now remaining could be answered within carefully designed preclini cal and clinical studies.