Clinical and Prognostic Significance of Cell Sensitivity to Chemotherapy Detected In Vitro on Treatment Response and Survival of Leukemia Patients

Abstract

Multidrug resistance (MDR) is a major challenge in leukemia treatment. The objective of this study was to identity predictors of MDR to allow for rapid and economical assessment of the efficacy of planned antitumor therapy for leukemia patients. The study included 113 patients with acute and chronic leukemias. Prior to antitumor therapy, we measured the sensitivity of tumor cells of patients to the panel of chemotherapeutic drugs, together with MDR1 mRNA and P-glycoprotein (P-gp) expression as one of the mechanisms of MDR, and compared these data with the response to therapy. The scales for leukemia patients according to therapy response, drug sensitivity of tumor cells, MDR1 mRNA and P-gp levels, and the presence of unfavorable immunological and cytogenetic markers were introduced for subsequent correlation analysis. We show that the drug resistance of tumor cells of leukemia patients estimated in vitro at diagnosis correlates with a poor response to chemotherapy and is usually combined with aberrant and immature immunological markers, cytogenetic abnormalities, and a high expression of MDR1 mRNA and P-gp. All together, these factors indicate unfavorable prognosis and low survival of leukemia patients. Thus, the sensitivity of tumor cells to chemotherapeutic drugs measured in vitro at diagnosis may have prognostic value for individual types of leukemia.

Drug responsiveness of leukemic cells detected in vitro at diagnosis correlates with therapy response and survival in patients with acute myeloid leukemia

“…Next, we developed appropriate scales for subsequent correlation analysis (see Table S2 ) as described in Reference 9 , and all patients were scaled according to the responsiveness of their tumor cells to chemotherapeutic drugs, therapy response, and expression of immunological markers (Table 1 ).…”

“…10 The diagnosis was confirmed by clinical, laboratory, and instrumental analysis according to the standard diagnostic protocols for AML 5 , 11 and formulated on the base of the WHO classification of tumors of hematopoietic and lymphoid tissues. 12 Immunophenotyping and cytogenetic analysis were performed before the start of treatment as described in Reference 9 . Demographic data including age, gender, date of presentation, time of relapse, and mortality were obtained from medical records or from institutional information databases.…”

“…Peripheral blood (PB) and/or bone marrow (BM) samples were obtained from leukemia patients ( n = 37) at diagnosis before chemotherapy as described previously 9 and were transported to the laboratory for in vitro studies within 3 hours of material collection.…”

“…Thereafter, the absorbance was measured spectrophotometrically using Multiscan RC (Labsystems, Finland) at 450 and 620 nm. The concentration of cytostatics that caused the death of 50% of tumor cells (IC 50 ) was calculated as described in Reference 9 .…”

“…8 Previously, we have shown that the drug responsiveness of tumor cells detected in vitro at diagnosis correlates with the therapy response and established prognostic markers in leukemia patients. 9 The most significant correlations were identified for AML: patients with tumor cell resistance to chemotherapeutic drugs demonstrated a poor response to standard chemotherapy and carried immature and aberrant immunological markers and cytogenetic abnormalities in tumor cells associated with an unfavorable prognosis for AML patients. 9 The aim of the present study was to prove our conception that an evaluation of the initial responsiveness of tumor cells to chemotherapeutic drugs in vitro can be useful in predicting the therapy response of leukemia patients and to assign the most effective antitumor treatment.…”