Cytotoxic efficacy of bendamustine in human leukemia and breast cancer cell lines.
OBJECTIVE
The purpose of this study was to characterise bendamustine's cytotoxic and apoptotic activity in a panel of leukemia and breast cancer cell lines in comparison to its clastogenicity in murine bone marrow.


METHODS
The cytotoxic effect of bendamustine was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT)-dye reduction assay. Induction of apoptosis was evidenced by DNA gel electrophoresis, nuclear staining, Western blot poly-(adenosine diphosphate-ribose) polymerase (PARP) cleavage, and flow cytometry. As a measure of hematological toxicity, the formation of chromosomal aberrations was investigated in bone marrow cells isolated from mice treated with low non-toxic doses of bendamustine and lomustine.


RESULTS
Bendamustine was preferably active against leukemic cells of lymphoid origin and was found to induce apoptosis in SKW-3 and BV-173 cells as shown by oligonucleosomal DNA and nuclear fragmentation, PARP cleavage, and formation of a sub-G1 fraction. Myeloid and breast carcinoma cell lines were resistant towards bendamustine with the exception of HL-60 cells which exhibit an intermediate sensitivity. Bendamustine was found to have a very low clastogenic effect as compared with equimolar doses of lomustine.


CONCLUSIONS
Taken together, the mode of action of bendamustine includes induction of apoptosis. The specific spectrum of activity and the unexpectedly low clastogenicity support the hypothesis that bendamustine in not a typical alkylating agent but exerts an additional mode of action, possibly as a purine antimetabolite.
Konstantinov
S M
SM
Lab. for Experimental Chemotherapy, Dept. of Pharmacology and Toxicology, Faculty of Phamacy at the Medical University of Sofia, 2 Dunav St., 1000 Sofia, Bulgaria. Pgen@vmei.acad.bg
Kostovski
A
A
Topashka-Ancheva
M
M
Genova
M
M
Berger
M R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000069461:Bendamustine Hydrochloride; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride