In vitro cross-resistance to nucleoside analogues and inhibitors of topoisomerase 1 and 2 in acute myeloid leukemia

Abstract

Only about one third of all patients with acute myeloid leukemia (AML) will be cured by common chemotherapy regimens. Susceptibility towards chemotherapy either of the leukemic bulk or the leukemic stem cell is considered the major determining parameter for long-term outcome. The purpose of the present study was to investigate whether chemoresistance was correlated between different antileukemic drugs or not. We determined the lethal concentration of chemotherapy necessary to reduce viability of cells to 50% compared to untreated control (LC50) as a surrogate marker of chemotherapy susceptibility of six established chemotherapeutic agents [cytarabine (median 0.83 microg/ml), daunorubicine (0.09 microg/ml), idarubicine (0.03 microg/ml), mitoxantrone (0.05 microg/ml), etoposide (4.81 microg/ml), and topotecan (0.14 microg/ml)] in an overall number of 147 samples from consecutive patients with AML by WST-1 assay in vitro. We found that susceptibility to chemotherapy was significantly correlated between all six agents (all p values < 0.01). A homogenous response of the blast populations was significantly correlated to high chemoresistance. These data indicate that cross-resistance in AML against antileukemic drugs exists between agents with different modes of action and seems not to be mediated by drug-specific resistance mechanisms but rather by more generalized death-defying features of the affected cells (e.g., inhibited apoptosis).

Drug cross‐resistance and therapy‐induced resistance in chronic lymphocytic leukaemia by an enhanced method of individualised tumour response testing

“…Almost all published reports on cross‐resistance recorded a P ‐value alongside the r ‐values (Kivekas et al , 2002; Lofgren et al , 2005; Styczynski et al , 2005; Hubeek et al , 2006; Fiegl et al , 2008; Lindhagen et al , 2008). Unfortunately, statistical tests of correlation are designed to determine the strength of a correlation – in this case, the likelihood that two drugs have the same or similar action (the null hypothesis being no correlation).…”

“…Thus, in CLL it is generally agreed that fludarabine and cladribine are cross-resistant, as patients resistant 'in vivo' to the former had a poor response rate to the latter (Juliusson et al, 1992;O'Brien et al, 1994). Laboratory studies show similar results with the advantage that ex vivo experiments can be performed simultaneously as opposed to having to be sequential in the patient (Fiegl et al, 2008). Cross-resistance in vitro, however, has generally been performed on relatively small numbers of patients (Lindhagen et al, 2008) giving potentially dubious results.…”

Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia

“…Some previous studies reported that patient samples with a high ex vivo drug resistance towards Ara C were not only resistant towards other deoxynucleotide analogues (e.g., fludarabine or gemcitabine) [18], but also towards other chemotherapeutics with different modes of action (such as VP16 or DNR) [19,20]. An intrinsic property of leukemic cells that is thought to play an important role in resistance to Ara C, is the ability to transport the drug across the plasma membrane in both directions [21].…”

5-diphenylacetamido-indirubin-3′-oxime as a novel mitochondria-targeting agent with anti-leukemic activities

“…However, a number of problems have been raised by the evasion of leukemia cells from anti‐cancer drugs and acquisition of resistance in leukemia cure . A serious matter is that surviving cells from first‐line chemotherapy evolve into more malignant cancer cells that become less sensitive to re‐induction regimens . Therefore, discovering a novel class of medicine with a different killing mechanism from those of established drugs is required.…”