Enhanced efficacy of gemcitabine in combination with anti-CD20 monoclonal antibody against CD20+ non-Hodgkin's lymphoma cell lines in vitro and in scidmice

Mitchell R Smith,Coleman Obasaju,Fang Jin,Indira Joshi

doi:10.1186/1471-2407-5-103

Mitchell R Smith, Coleman Obasaju + Show 2 more

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https://doi.org/10.1186/1471-2407-5-103

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Journal: BMC Cancer	Publication Date: Aug 18, 2005
Citations: 41	License type: cc-by

Affiliation: Fox Chase Cancer Center, Eli Lilly (United States)

Abstract

BackgroundDespite exciting new targeted therapeutics against non-Hodgkin's lymphoma (NHL), chemotherapy remains a cornerstone of therapy. While purine nucleoside analogs have significant activity in low grade NHL, the pyrimidine nucleoside analog gemcitabine has been less extensively studied, but has important activity. Use of the anti-CD20 monoclonal antibody rituximab in combination with chemotherapy for B-NHL is becoming prevalent in clinical practice, but has not been extensively studied in pre-clinical models.MethodsWe have tested the activity of gemcitabine ± rituximab in vitro and in scid/human NHL xenograft models. We used two t(14;18)+, CD20+ follicular B cell NHL cell lines, DoHH2 a transformed NHL line and WSU-FSCCL isolated from pleural fluid of a patient with indolent NHL.ResultsGemcitabine is cytotoxic to DoHH2 and WSU-FSCCL cells in vitro, and the IC50 is 2–3 fold lower in the presence of rituximab. Apoptosis is also enhanced in the presence of rituximab. Clearance of NHL cells from ascites in scid mice is prolonged by the combination, as compared with either agent alone. Most importantly, survival of scid mice bearing human NHL cells is significantly prolonged by the combination of gemcitabine + rituximab.ConclusionBased on our pre-clinical data showing prolonged survival of mice bearing human lymphoma cell line xenografts after treatment with gemcitabine + anti-CD20 antibody, this combination, expected to have non-overlapping toxicity profiles, should be explored in clinical trials.

Highlights

Despite exciting new targeted therapeutics against non-Hodgkin's lymphoma (NHL), chemotherapy remains a cornerstone of therapy
Non-Hodgkin's lymphoma (NHL) is increasing in incidence and is the fifth most common malignancy in the U.S Despite novel targeted biologic treatment options, chemotherapy remains an important component of therapy
Apoptosis was determined by dual staining of 1 × 105 intact cells in 100 μl calcium binding buffer containing 5 μl of fluoroscein isothiocyanate (FITC)labeled annexin V (Pharmingen) and 5 μg/ml propidium iodide (PI) for 15 minutes in the dark, followed by analysis by flow cytometry (FACScan)

Summary

Introduction

Despite exciting new targeted therapeutics against non-Hodgkin's lymphoma (NHL), chemotherapy remains a cornerstone of therapy. While purine nucleoside analogs have significant activity in low grade NHL, the pyrimidine nucleoside analog gemcitabine has been less extensively studied, but has important activity. Non-Hodgkin's lymphoma (NHL) is increasing in incidence and is the fifth most common malignancy in the U.S Despite novel targeted biologic treatment options, chemotherapy remains an important component of therapy. Gemcitabine is a pyrimidine nucleoside analog with clinical anti-cancer activity. Purine nucleoside analogs such as (page number not for citation purposes). BMC Cancer 2005, 5:103 http://www.biomedcentral.com/1471-2407/5/103 fludarabine, cladribine and pentostatin have been extensively studied and have significant activity against certain non-Hodgkin's lymphoma subtypes, indolent forms. The precise place of gemcitabine in the therapeutic armamentarium for NHL remains to be elucidated

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