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.

[1]  J. Ritter,et al.  Die Corticosteroid-abhängige Dezimierung der Leukämiezellzahl im Blut als Prognosefaktor bei der akuten lymphoblastischen Leukämie im Kindesalter (Therapiestudie ALL-BFM 83) , 1987 .

[2]  R. Pieters,et al.  DRUG SENSITIVITY ASSAYS IN LEUKAEMIA AND LYMPHOMA , 1990, British journal of haematology.

[3]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[4]  R. Pieters,et al.  In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. , 1995, Blood.

[5]  K. Somberg,et al.  Acute tumor lysis syndrome after intrathecal methotrexate administration , 1991, Cancer.

[6]  R. Pieters,et al.  In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia. , 1997, Blood.

[7]  R. Pieters,et al.  IN VITRO RESISTANCE TO CYTOSINE ARABINOSIDE, NOT TO DAUNORUBICIN, IS ASSOCIATED WITH THE RISK OF RELAPSE IN DE NOVO ACUTE MYELOID LEUKAEMIA , 1996, British journal of haematology.

[8]  R. Pieters,et al.  Cellular drug resistance profiles that might explain the prognostic value of immunophenotype and age in childhood acute lymphoblastic leukemia. , 1993, Leukemia.

[9]  D. Duval,et al.  Heterogeneity of the in vitro responses to glucocorticoids in acute leukemia. , 1980, Cancer research.

[10]  Y. Bertrand,et al.  Systemic effect of intrathecal methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  R. Pieters,et al.  In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions , 1990 .

[12]  J. Baxter,et al.  Tissue effects of glucocorticoids. , 1972, The American journal of medicine.

[13]  R. Pieters,et al.  Different cellular drug resistance profiles in childhood lymphoblastic and non-lymphoblastic leukemia: a preliminary report. , 1994, Leukemia.

[14]  M. Cline,et al.  Prediction of in vivo cytotoxicity of chemotherapeutic agents by their in vitro effect on leukocytes from patients with acute leukemia. , 1968, Cancer research.

[15]  R. Pieters,et al.  Clinical and cell biological features related to cellular drug resistance of childhood acute lymphoblastic leukemia cells. , 1995, Leukemia & lymphoma.

[16]  R. Pieters,et al.  Everything you always wanted to know about cellular drug resistance in childhood acute lymphoblastic leukemia. , 1997, Critical reviews in oncology/hematology.

[17]  R. Pieters,et al.  Adaptation of the rapid automated tetrazolium dye based (MTT) assay for chemosensitivity testing in childhood leukemia. , 1988, Cancer letters.

[18]  S. Iacobelli,et al.  Clinical implications of glucocorticoid receptor studies in childhood acute lymphoblastic leukemia. , 1980, Blood.

[19]  H. Gralnick,et al.  The Morphological Classification of Acute Lymphoblastic Leukaemia: Concordance among Observers and Clinical Correlations , 1981, British journal of haematology.

[20]  L. Smets,et al.  Prognostic implication of hyperdiploidy as based on DNA flow cytometric measurement in childhood acute lymphocytic leukemia--a multicenter study. , 1987, Leukemia.

[21]  A. Ho,et al.  Therapeutic and prognostic implications of glucocorticoid receptors and terminal deoxynucleotidyl transferase in acute leukemia. , 1982, Leukemia research.

[22]  R. Pieters,et al.  Drug combination testing in acute lymphoblastic leukemia using the MTT assay. , 1995, Leukemia research.

[23]  R. Pieters,et al.  Glucocorticoid resistance in childhood leukemia. , 1994, Leukemia & lymphoma.

[24]  B. Chabner,et al.  ALTERED PLASMA PHARMACOKINETICS OF METHOTREXATE ADMINISTERED INTRATHECALLY , 1975, The Lancet.

[25]  Dedrick Rl,et al.  Clinical pharmacology of intrathecal methotrexate. I. Pharmacokinetics in nontoxic patients after lumbar injection. , 1977 .

[26]  M. Schrappe,et al.  Therapy results in five ALL-BFM studies since 1970: implications of risk factors for prognosis. , 1987, Haematology and blood transfusion.

[27]  R. Pieters,et al.  In vitro chemosensitivity assessed with the MTT assay in childhood acute non-lymphoblastic leukemia. , 1995, Leukemia.

[28]  R. Pieters,et al.  Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia , 1991, The Lancet.

[29]  J. V. van Dongen,et al.  Contribution of electron microscopy to the classification of minimally differentiated acute leukemias in children. , 1993, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[30]  M. Gobbi,et al.  Glucocorticoid receptor and in vitro sensitivity to steroid hormones in human lymphoproliferative diseases and myeloid leukemia , 1982, Cancer.

[31]  M. Schrappe,et al.  Cytoreduction and prognosis in childhood acute lymphoblastic leukemia. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  D.,et al.  Regression Models and Life-Tables , 2022 .

[33]  M. Lippman,et al.  Clinical implications of glucocorticoid receptors in human leukemia. , 1978, Cancer research.

[34]  R. Pieters,et al.  In vitro drug sensitivity of normal peripheral blood lymphocytes and childhood leukaemic cells from bone marrow and peripheral blood. , 1991, British Journal of Cancer.

[35]  R. Pieters,et al.  Mononuclear cells contaminating acute lymphoblastic leukaemic samples tested for cellular drug resistance using the methyl-thiazol-tetrazolium assay. , 1994, British Journal of Cancer.

[36]  J H Goldie,et al.  The genetic origin of drug resistance in neoplasms: implications for systemic therapy. , 1984, Cancer research.

[37]  R. Dedrick,et al.  Clinical pharmacology of intrathecal methotrexate. I. Pharmacokinetics in nontoxic patients after lumbar injection. , 1977, Cancer treatment reports.

[38]  R. Pieters,et al.  Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study. , 1995, Blood.

[39]  R. Pieters,et al.  Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. , 1998, Blood.