scholarly journals Evidence of a role for functional heterogeneity in multidrug resistance transporters in clinical trials of P-glycoprotein modulation in acute myeloid leukemia

2018 ◽  
Vol 96 (1) ◽  
pp. 57-66 ◽  
Author(s):  
John F. Marcelletti ◽  
Branimir I. Sikic ◽  
Larry D. Cripe ◽  
Elisabeth Paietta
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Functional Heterogeneity ◽  
P Glycoprotein ◽  
Multidrug Resistance Transporters ◽  
Acute Myeloid

P‐glycoprotein and multidrug resistance‐associated protein‐1 expression in acute myeloid leukemia: Biological and prognosis implications

2020 ◽  
Vol 42 (5) ◽  
pp. 594-603
Author(s):  
Lenilton Silva da Silveira Júnior ◽  
Victor de Lima Soares ◽  
Alessandra Suelen Jardim da Silva ◽  
Erica Aires Gil ◽  
Maria das Graças Pereira de Araújo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
P Glycoprotein ◽  
Acute Myeloid

Triggering Noncycling Hematopoietic Progenitors and Leukemic Blasts to Proliferate Increases Anthracycline Retention and Toxicity by Downregulating Multidrug Resistance

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2414-2423 ◽  
Author(s):  
Mariëlle E.P. Smeets ◽  
Reinier A.P. Raymakers ◽  
Gerty Vierwinden ◽  
Arie H.M. Pennings ◽  
Hans Wessels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Proliferation Rate ◽  
Related Protein ◽  
Hematopoietic Progenitors ◽  
P Glycoprotein ◽  
Cd34 Cells ◽  
Normal Human ◽  
Acute Myeloid

Expression of the multidrug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-related protein (MRP) decrease cellular retention and consequently cytotoxicity of anthracyclines. MDR is expressed on normal human hematopoietic progenitors and leukemic blasts. Normal CD34+ progenitors showed rhodamine efflux in 20% to 30% of the cells, which could be blocked by verapamil. These cells appeared noncycling, in contrast to the proliferating rhodamine bright (RhoB) cells. We postulated that MDR expression can be downregulated by proliferation induction. Triggering rhodamine dull (RhoD) CD34+ cells to proliferate indeed resulted in a higher rhodamine retention and significantly decreased efflux modulation by verapamil (P = .04). Also in acute myeloid leukemia (AML), the proliferation rate (percentage S/G2+M and Iododeoxyuridine labelings index) was significantly less in the RhoD blasts (P ≤ .008) and proliferation induction of RhoD blasts resulted in increased rhodamine retention. Anthracycline cytotoxicity was less for RhoD than RhoB cells in both normal progenitors and leukemic blasts. Proliferation induction of the RhoD cells resulted in increased anthracycline sensitivity. We conclude that noncycling progenitors, both normal and leukemic, have a relatively high MDR expression. Triggering these cells into proliferation downregulates MDR expression. These findings can be exploited to overcome MDR in the treatment of AML patients.

New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Martin S. Tallman
Keyword(s):  
Older Adults ◽  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Farnesyltransferase Inhibitors ◽  
Younger Adults ◽  
The Impact ◽  
Acute Myeloid

Abstract The prognosis for younger adults (≤ 55–60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%–80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%–40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%–55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation. Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPα, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.

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