Cell proliferation is related to in vitro drug resistance in childhood acute leukaemia

Abstract

Bone marrow and peripheral blood samples from 362 patients with acute lymphoblastic leukaemia (ALL) proliferating cell and 90 patients with acute myeloid leukaemia (AML) were analysed for S-phase fractions, Ki67 antigen, and proliferating cell nuclear antigen expression. The S-phase fractions were correlated with in vitro drug resistance to 15 different anticancer agents. Leukaemia cells isolated from bone marrow had higher S-phase fractions than leukaemia cells isolated from peripheral blood (in initial ALL, median values resp. 6.9 and 2.7%, in initial AML resp. 5.3 and 1.3%; both Po0.01). Relapse ALL samples derived from bone marrow showed increased S-phase fractions (median 9.9%) compared with initial ALL samples (median 6.9%; Po0.01). ALL samples obtained at initial diagnosis showed higher S-phase fractions (median 6.9%) and higher Ki67 expression (median 30%) than initial AML samples (median resp. 5.3 and 14%; both Po0.05). The S-phase fractions were not related to white blood cell count, age, or gender. Within initial ALL, the S-phase fraction correlated significantly but modestly strong (r ¼ 0.3 -0.5; Po0.05) with sensitivity to antimetabolites (cytarabine, mercaptopurine, thioguanine), L-asparaginase, teniposide, and vincristine. Similar results were found within subgroups of initial ALL (nonhyperdiploid and common/precursor-B-lineage ALL). In relapsed ALL and AML such correlations were not found. In conclusion, cell proliferation differs between leukaemia subgroups and increased proliferation is associated with increased in vitro sensitivity to several anticancer agents in initial ALL.

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

“…This is in accordance with the general notion of a correlation between high proliferation and increased anticancer drug sensitivity (Valeriote and van Putten, 1975;Kaaijk et al, 2003). Some limitations of the study should be discussed.…”

Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

“…Interestingly, it has been noted earlier that the proportion of cycling cells is increased in relapsed versus initial ALL (28). Our data now reveal that this mainly applies to very early relapse, whereas late relapse displays an even lower fraction of cycling cells in the bone marrow than samples at first presentation (median, 3.9% S phase cells at late relapse versus 6.9% at first presentation in the study of Kaaijk et al;ref.…”

“…At ALL relapse, however, we consider leukemic blasts that have escaped frontline treatment and progressed in malignancy reflected by higher rates of poor or nonresponse to treatment in particular in very early relapsed patients (4). Accordingly, higher proportions of cycling cells did not correlate with in vitro chemosensitivity at ALL relapse (28). At relapse, leukemic blasts may have gained signaling pathways that enable a more aggressive growth of cancer cells.…”

“…28 and references therein). However, in in vitro experiments, an increased proliferation rate was associated with good response to treatment (28).…”

“…28 and references therein). However, in in vitro experiments, an increased proliferation rate was associated with good response to treatment (28). In initial ALL, a higher fraction of proliferating cells seems to result in a higher efficacy of chemotherapeutic drugs targeting the cell division cycle.…”