As an important determinant of the response to chemotherapy, measurements of cellular drug resistance may provide prognostically significant information, which could be useful for optimal risk-group stratification. The objective of this report is to determine the relation between in vitro resistance to 12 drugs, measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and long-term clinical response to chemotherapy in 152 children with newly diagnosed acute lymphoblastic leukemia. At risk-group stratified analyses, in vitro resistance to prednisolone, L-asparaginase, and vincristine were each significantly (P < .01) related to the probability of disease-free survival (pDFS) after combination chemotherapy. The combination of data for prednisolone, L-asparaginase, and vincristine provided a drug-resistance profile with prognostic independent significance superior to that of any single drug or any other factor. The 3-years pDFS was 100% for the group with the most sensitive profile, 20% of all patients, 84% (SE 6%) for the group with an intermediately sensitive profile, 40% of all patients, and 43% (SE 8%) for the remaining group with the most resistant profile (P < .001). In conclusion, the extent of in vitro cellular resistance to prednisolone, L-asparaginase, and vincristine, measured using the MTT assay, was significantly related to the clinical response to combination chemotherapy. Treatment failure in newly diagnosed childhood ALL can be predicted based on cellular drug resistance data.

Bcl-2 over-expression has been shown to inhibit apoptosis induced by a variety of stimuli, whereas a predominance of Baxa to Bcl-2 accelerates apoptosis upon apoptotic stimuli. We sought to study the relevance of these apoptotic regulating gene products in leukaemia. In a panel of leukaemia and lymphoma cell lines (HL60, DoHH2, CEM C7, L1210 and S49), the Baxa-to-Bcl-2 ratio as assessed by Western-blot analysis correlated with sensitivity to dexamethasone treatment. In addition, in HAbaxa-transfected CEM C7 clones, a similar correlation was found for dexamethasone and thapsigargin sensitivity. In bone-marrow aspirates from patients with childhood acute lymphoblastic or myelocytic leukaemia (ALL, n 5 48; AML, n 5 8), the Bcl-2 and Baxa levels were highly variable, but well within the range found in the Baxa transfectants and in the established cell lines. Bcl-2 levels were lower in T-than in B-lineage ALL, which could be ascribed to simultaneous inverse relation between Bcl-2 and WBC. By contrast, Baxa:Bcl-2 was independent of any presenting feature and was largely dependent on Baxa levels. Results suggest that Baxa:Bcl-2, rather than Bcl-2 alone is important for the survival of drug-induced apoptosis in leukemic cell lines and ALL. Int. J. Cancer 71:959-965, 1997.r 1997 Wiley-Liss, Inc.Bcl-2 was initially identified because of its involvement in the chromosomal translocation t(14;18), resulting in high levels of the 26-kDa Bcl-2 protein. Bcl-2 over-expression was subsequently shown to inhibit apoptosis (for review, see Reed, 1995). Moreover, over-expression of Bcl-2 has been implicated in the insensitivity of cells to a variety of anti-cancer drugs, especially those used in the chemotherapy of childhood ALL, notably glucocorticoids (GC) (Miyashita and Reed, 1992;Sentman et al., 1991;Smets et al., 1994). Bcl-2 may, therefore, define a new category of drugresistance genes regulating the physiological cell-death pathway (Reed, 1995). Accordingly, increased levels of Bcl-2 may be associated with poor prognosis in leukaemia by a dual action. First, it could expand the population of circulating blasts by promoting their survival and, second, it could antagonize response to chemotherapy by inhibiting steroid hormone-and cytostatic-drug-induced apoptosis. Attesting to this view, high expression of Bcl-2 has been associated with high WBC and poor prognosis in adult AML (Campos et al., 1993).In childhood ALL, the role of Bcl-2 is not clear yet. A number of studies (Campana et al., 1993;Gala et al., 1994;Coustan-Smith et al., 1996) agree that high Bcl-2 expression is the rule in ALL blasts, compared with their normal precursors, while no study found an association between Bcl-2 levels and the presenting features immunophenotype, ploidy and WBC. Increased expression of Bcl-2 was not found to correlate with prognosis in one study (Gala et al., 1994), but correlated with poor initial response to chemotherapy in another report (Maung et al., 1994). By contrast, CoustanSmith et al. (1996) found that elevated levels of Bcl-2 we...

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