Activity of bortezomib in adult de novo and relapsed acute myeloid leukemia.
BACKGROUND
Bortezomib is an inhibitor of proteasome and NF-kappaB, with activity in various solid tumors and hematological malignancies.


OBJECTIVE
The aim of the study was the analysis of in vitro drug resistance to bortezomib and other anticancer drugs in de novo and relapsed adult acute myeloid leukemia (AML).


METHODS
The leukemic cells of 46 adult patients with AML were tested for the in vitro drug resistance profile. The group included 20 de novo and 26 relapsed AML patients, among whom, 12 relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) and 4 after autologous HSCT. The MTT assay was performed for 21 drugs. Expression of P-glycoprotein (PGP), multidrug resistance-associated protein-1 (MRP1) and lung resistance protein (LRP) proteins was measured by flow cytometry.


RESULTS
No significant differences in drug resistance were found for all tested drugs between de novo and relapsed AML samples, while expression of PGP, MRP1 and LRP was higher in relapsed patients. Patients with refractory or relapsed disease, had higher resistance of myeloblasts to cyclophosphamide (RR = 2.4, p = 0.050), and better sensitivity to busulfan (RR = 0.4, p = 0.054) and topotecan (RR = 0.4, p = 0.031). Those who have died due to refractory/relapsed disease (n = 16) had better sensitivity to bortezomib (RR = 0.6, p = 0.046) and treosulfan (RR = 0.1, p = 0.018).


CONCLUSIONS
In vitro drug resistance in relapsed adult AML is comparable to that in de novo disease. Activity in vitro of bortezomib might be a rationale for its use in refractory/relapsed AML adult patients.
Gil
Lidia
L
Department of Hematology, University of Medical Sciences, Poznan, Poland.
Styczynski
Jan
J
Dytfeld
Dominik
D
Debski
Robert
R
Kazmierczak
Maciej
M
Kolodziej
Beata
B
Rafinska
Beata
B
Kubicka
Malgorzata
M
Nowicki
Adam
A
Komarnicki
Mieczyslaw
M
Wysocki
Mariusz
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000378:metabolism; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011719:Pyrazines; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C421109:multidrug resistance-associated protein 1