Prednisolone Resistance Research Articles

Lack of cross-resistance between prednisolone and methotrexate in childhood acute lymphoblastic leukemia? A preliminary analysis.

We studied the cross-resistance between prednisolone (PRD) and methotrexate (MTX) in children with newly diagnosed acute lymphoblastic leukemia (ALL). This was done because of a previous observation that such patients could show a good clinical response to systemic PRD monotherapy plus intrathecal MTX, despite in vitro PRD resistant ALL cells (as determined with the MTT assay). This suggests an antileukemic effect of MTX, and thus the lack of cross-resistance between PRD and MTX. A systemic antileukemic effect of intrathecally administered MTX has been reported in the literature. Clinical good responders with PRD resistant ALL cells (n = 15) did not show unfavorable MTX-polyglutamylation nor unfavorable low inhibition of thymidylate synthase by MTX, as compared to a heterogeneous group of newly diagnosed ALL children (n = 47). In addition, we did not find a significant correlation between these two parameters and in vitro PRD resistance within the clinical good responders with PRD resistant ALL cells. In conclusion, we did not find a significant cross-resistance between PRD and MTX in vitro. It therefore may be that the good clinical response to systemic PRD plus intrathecal MTX in patients with in vitro PRD resistant ALL cells was caused by a systemic antileukemic activity of the intrathecally administered MTX.

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 measurement of cellular drug resistance may provide clinically relevant information. Our objectives in this study were to determine the relationship between in vitro resistance to prednisolone (PRD) measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and (1) short-term clinical response to systemic PRD monotherapy, (2) long-term clinical outcome after combination chemotherapy within all patients and within the subgroups of clinical good and poor responders to PRD, and (3) in vitro resistance to 12 other drugs in 166 children with newly diagnosed acute lymphoblastic leukemia (ALL). The 12 clinical poor PRD responders had ALL cells that were median 88-fold more in vitro resistant to PRD than 131 good responders (P = .013). Within all patients, increased in vitro resistance to PRD predicted a significantly worse long-term clinical outcome, at analyses with and without stratification for clinical PRD response, and at multivariate analysis (P </= .001). Within both the clinical good and poor responder subgroups, increased in vitro resistance to PRD was associated with a worse outcome, which was significant within the group of clinical good responders (P < .001). LC50 values, ie, lethal concentrations to 50% of ALL cells, for PRD and each other drug correlated significantly with those of all other 12 drugs, with an average correlation coefficient of 0.44 (standard deviation 0.05). The highest correlations were found between structurally related drugs. In conclusion, in vitro resistance to PRD was significantly related to the short-term and long-term clinical response to chemotherapy, the latter also within the subgroup of clinical good responders to PRD. There was a more general in vitro cross-resistance between anticancer drugs in childhood ALL, although drug-specific activities were recognized.

Biological and clinical significance of in vitro prednisolone resistance in adult acute lymphoblastic leukaemia.

It has been reported that in vitro prednisolone (PDN) resistance provides a prognostic value in childhood acute lymphoblastic leukaemia (ALL). This study aimed at investigating the biological and clinical significance of in vitro PDN resistance in adult ALL. Blast cells from 30 patients were exposed to PDN (0.1 microM-35 microM) and cytotoxicity was determined by the soluble tetrazolium formazan 2,3-bis (2-methoxy-4-nitro-5-sulphophenyl)-5-[(phenylamino) carbamyl]-2H-tetrazolium hydroxyde (XTT) colorimetric assay. The IC50 (defined as the drug concentration that results in 50% growth inhibition) varied greatly among the samples, from 0.3 microM to > 35 microM; 15 microM was subsequently chosen as IC50-cut-off point between in vitro resistant and sensitive cases. PDN-induced cytotoxicity was significantly related to apoptosis, as demonstrated by regression analysis; in sensitive cases, however, the percentage of apoptotic cells after in vitro PDN treatment was significantly increased compared with control (p = 0.002). Immunofluorescence evaluation of intracellular BCL-2 protein showed an equal percentage of positive cells in the two groups, but in resistant cells a higher mean fluorescence intensity (p = 0.04) was demonstrated. In vitro sensitive and resistant patients did not display differences in clinical characteristics, in cytological, karyotypic and immunophenotypic features and in the outcome of induction therapy. Disease-free survival (DFS), however, was significantly better in sensitive patients (p = 0.02).