In vitro induction of apoptosis of neoplastic cells in low-grade non-Hodgkin's lymphomas using combinations of established cytotoxic drugs with bendamustine.

Abstract

BACKGROUND AND OBJECTIVES:

Regulation of apoptotic cell death is being increasingly recognized as a mechanisms by which cytostatic agents mediate tumor cell death. Preliminary clinical studies with bendamustine, an alkylating agent with a purine nucleus, provide strong evidence that this drug is a highly effective cytostatic in low grade lymphomas. Therefore, we investigated the in vitro activity of bendamustine in combination with other established cytotoxic drugs.

DESIGN AND METHODS:

2 lines (DOHH-2, WSU-NHL) and mononuclear cells (MNC) from patients with leukemic low-grade B-non-Hodgkin's lymphoma (NHL) (n=10), T-NHL (n=7) and chronic lymphocytic leukemia (CLL) (n=12). Apoptosis (7-AAD), depolarization of mitochondrial membrane potential (MMP, JC-1), caspase-3-activity (FIENA) and cell proliferation (XTT/WST-1) were determined. Several incubation times and drug dosages (for IC(30/50/75/90)) were studied. Synergistic, additive or antagonistic effects were calculated by a median plot effect and the combination index (CI) method.

RESULTS:

In general, combinations of bendamustine with mitoxantrone or doxorubicin resulted in antagonistic effects in the tested cell lines and the MNC from the patients. CI-calculation failed in these cases since there was not a sufficient dose response. On the other hand, the combination of bendamustine with 2-CdA showed synergistic in vitro activity on the tested cell lines, neoplastic lymphocytes from patients with peripheral T-cell lymphomas and partially on MNC from patients with CLL and B-NHL. The antagonism of the combination of bendamustine and anthracyclines appeared to be due to inhibition of depolarization of mitochondrial-membrane potential and caspase-3-activity during apoptosis of the studied cell lines.

INTERPRETATION AND CONCLUSIONS:

In conclusion, our results suggest that schedules using combinations of bendamustine and anthracyclines should not be recommended for the treatment of low-grade NHL, whereas bendamustine combined with 2-CdA could be considered for the development of future treatment strategies.

• Authors: K U Chow, S Boehrer, K Geduldig, A Krapohl, D Hoelzer, P S Mitrou, E Weidmann
• Journal: Haematologica (Haematologica) Vol. 86 Issue 5 Pg. 485-93 (May 2001) ISSN: 0390-6078 [Print] Italy
• PMID: 11410411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nitrogen Mustard Compounds
• Bendamustine Hydrochloride

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Bendamustine Hydrochloride
• Drug Interactions
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, pathology)
• Lymphoma, Non-Hodgkin (drug therapy, pathology)
• Nitrogen Mustard Compounds (pharmacology, therapeutic use)
• Tumor Cells, Cultured (drug effects)