Potentiation of fludarabine cytotoxicity on non-Hodgkin's lymphoma by pentoxifylline and rituximab

Abstract

Background: Fludarabine has become a drug of prominent use in hematopoietic malignancies exhibiting indolent growth profiles. Some studies show, however, that nearly 50% of patients are fludarabine-resistant from the very onset of therapy. Others relapse after an initial response rarely lasting more than 2 years. For this reason, modulating agents have been considered for use with fludarabine to potentiate fludarabine cytotoxicity and circumvent drug resistance. The chimeric anti-CD20 monoclonal antibody, Rituximab (IDEC-C2B8), is used to treat patients with low grade and follicular B-cell non-Hodgkin's lymphoma. Rituximab is known to inhibit the cell progression of tumor B cells and to sensitize them to chemotherapeutic drugs. A slower cell progression may enhance the efficacy of fludarabine incorporation, thus increasing its cytotoxicity. Therefore, the use of fludarabine and Rituximab in combination could potentiate fludarabine cytotoxicity. The methylxanthine, pentoxifylline, disrupts DNA repair mechanisms within a cell by not allowing a cell to arrest at the G2/M checkpoint. By not allowing cells to repair fludarabine DNA incorporation, pentoxifylline was thought to increase fludarabine-induced cytotoxicity in tumor cells. We tested these hypotheses in vitro.

Materials and methods: Analysis of cytotoxicity was performed using the XTT assay on tumor cell lines and patient samples.

Results: Tumor cell models, including two B-cell non-Hodgkin's lymphoma cell lines and a T-cell leukemia cell line, were shown to respond more effectively to fludarabine therapy in the presence of Rituximab or pentoxifylline. Two freshly derived B-cell chronic lymphocytic leukemia patient samples were also seen to exhibit a better response with a combination of fludarabine and pentoxifylline than with either alone.

Conclusion: This study proves the hypothesis that Rituximab and pentoxifylline may provide a clinical approach to hinder the outgrowth of drug refractory tumor cells and achieve a longer period of remission.