Gemcitabine demonstrates in vitro activity against human B-cell chronic lymphocytic leukemia.
B-cell chronic lymphocytic leukemia (CLL) is the most common type of leukemia diagnosed in the Western Hemisphere and remains incurable with currently available therapy. In an attempt to identify new potential therapy for CLL, we explored the pre-clinical activity of gemcitabine in human B-CLL cells (n =11). Mononuclear cell isolates were exposed to varying concentrations of gemcitabine (0.01-100 microM) for 4, 24, and 96 h. Viability, as determined by the tetrazolium salt (MTT) assay, after a 4 h incubation with gemcitabine declined in 6 of 8 (75%) evaluable patients at a concentration < 30 microM (a physiologically attainable level), and 3 of 8 of the B-CLL cells had an LC50 (concentration where 50% loss of viability is observed) < 30 microM. At 4 days of drug exposure, 82% (9/11) of patients had an LC50 < 30 microM. Annexin-V/propidium iodine staining demonstrated apoptosis in CLL cells exposed to 30 microM of gemcitabine. Examination of changes in apoptosis related proteins demonstrated no significant change in bcl-2, bax or p53 protein expression with gemcitabine (23 microM) at 4, 24, or 48 h. These data demonstrate that gemcitabine has pre-clinical activity in B-CLL and supports its exploration as a single agent and in combination with other active agents in this disease.
Waselenko
J K
JK
Hematology/Oncology Service, Brooke Army Medical Center, FT Sam, Houston, TX, USA.
Grever
M R
MR
Shinn
C A
CA
Flinn
I W
IW
Byrd
J C
JC
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D051028:bcl-2-Associated X Protein; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003841:Deoxycytidine; D000093542:Gemcitabine