Cross-resistance and synergy with bendamustine in chronic lymphocytic leukemia.
Bendamustine (BEN) has structural similarities to an alkylating agent and a nucleoside analog, and effective against tumor cells that are resistant to standard therapy. In this study we compared the activities of BEN against that of the alkylating agent, chlorambucil (CLB), and the nucleoside analogs, fludarabine (FLU) and deoxyadenosine/pentostatin (dADO/PEN), in primary chronic lymphocytic leukemia (CLL) cells in vitro. Cross-resistance was observed between BEN, CLB and FLU, with previously treated patients or those with a deletion 17p being most resistant. In contrast, some resistant CLL cells retained moderate sensitivity to dADO/PEN. Like FLU and CLB, BEN induced apoptosis through both the mitochondrial and death receptor pathways. There was a greater increase in DNA double-strand breaks (DSB) following FLU, as compared to BEN and CLB. Synergistic cytotoxicity was seen on combining BEN or CLB with FLU or dADO/PEN, but not when combining BEN with CLB. These results demonstrate that BEN acts as an alkylating agent, demonstrates cross-resistance to CLB and FLU and resistance to cells with a del 17p. Synergistic cytotoxic activity was seen between BEN and dADO/PEN suggesting that the combination of BEN and PEN should be evaluated in the clinic.
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
Sara E F
SE
Kost
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada; University of Manitoba, Winnipeg MB, Canada.
Eric D J
ED
Bouchard
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
Élise
É
LaBossière
University of Manitoba, Winnipeg MB, Canada; Centre for Healthcare Innovation, Winnipeg, MB, Canada.
Xibiao
X
Ye
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
Michelle L
ML
Queau
University of Manitoba, Winnipeg MB, Canada.
William S
WS
Liang
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada; University of Manitoba, Winnipeg MB, Canada.
Versha
V
Banerji
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada; University of Manitoba, Winnipeg MB, Canada.
Spencer B
SB
Gibson
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada; University of Manitoba, Winnipeg MB, Canada.
Sachin
S
Katyal
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada; University of Manitoba, Winnipeg MB, Canada. Electronic address: jjohnsto@cancercare.mb.ca.
James B
JB
Johnston
D058892:Adenosine Deaminase Inhibitors; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000069461:Bendamustine Hydrochloride / Q000627:therapeutic use*; D002699:Chlorambucil / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D003839:Deoxyadenosines / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D015649:Pentostatin / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D058892:Adenosine Deaminase Inhibitors; D018906:Antineoplastic Agents, Alkylating; D003839:Deoxyadenosines; D002699:Chlorambucil; D015649:Pentostatin; D000069461:Bendamustine Hydrochloride; C058118:2'-deoxyadenosine
Bendamustine; Chemoresistance; Chronic lymphocytic leukemia; Drug synergy; Nucleoside analogs; Pentostatin