LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.
B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.
Mowery
Y M
YM
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Weinberg
J B
JB
Kennedy
M N
MN
Bond
K M
KM
Moore
J O
JO
Lanasa
M C
MC
Gockerman
J P
JP
Diehl
L F
LF
Pizzo
S V
SV
Cianciolo
G J
GJ
Friedman
D R
DR
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001896:Boron Compounds / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D011379:Prognosis; D011687:Purines / Q000494:pharmacology* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
C511928:2-amino-6-chloro-9-((5-dihydroxyboryl)pentyl)purine; D000970:Antineoplastic Agents; D001896:Boron Compounds; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D014740:Vidarabine; C024352:fludarabine