The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia.
As chronic lymphocytic leukemia (CLL) is characterized by overexpression of pro-survival BCL2, compounds that mimic its physiological antagonists, the BH3-only proteins, may have a role in treatment of this disease. ABT-737 is a BH3 mimetic compound that selectively targets BCL2 and BCLX(L). In the present work, we report that ABT-737 is highly effective (LC(50)<50 nM) as a single agent against most (21/30) primary CLL samples, but that a sizable minority is relatively insensitive. In vitro sensitivity to ABT-737 could not be simply predicted by the patients' clinical features, including response to prior therapy or known prognostic markers (CD38 expression, 17p deletion), or the relative expression of BCL2 family proteins (BCL2, MCL1, BAX, BIM). Strikingly, co-incubation with cytotoxic agents (dexamethasone, etoposide, fludarabine, doxorubicin) sensitized most CLL samples to ABT-737, but this could not be predicted by responses to either ABT-737 or the cytotoxic agent alone. Of 17 samples least sensitive to ABT-737, 13 were sensitized by co-treatment with at least one cytotoxic agent. These data indicate that combination of ABT-737 with a second anti-leukemic agent would improve response rates and suggest a potential role for combination therapies that include BH3 mimetics for the treatment of this disease.
Mason
K D
KD
Divisions of Cancer and Haematology and Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Khaw
S L
SL
Rayeroux
K C
KC
Chew
E
E
Lee
E F
EF
Fairlie
W D
WD
Grigg
A P
AP
Seymour
J F
JF
Szer
J
J
Huang
D C S
DC
Roberts
A W
AW
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D018716:Molecular Mimicry; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
C501332:ABT-737; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D014740:Vidarabine; C024352:fludarabine