Non-Hodgkin's lymphoma is a tumor consisting of malignant B-cell lymphocytes that presents with a spectrum of tumor grades and stages. Treatment strategies result in high response rates, however, eventually two-thirds of all tumors become treatment resistant and are fatal. Developments in molecular biology have shown that lymphoma malignant behavior is directly related to the balance between increased cellular proliferation and decreased cell death. Recently, widespread use of anti-CD-20 antibody for indolent lymphomas has demonstrated high levels of response, without the toxicity observed with chemotherapeutic agents. The mechanisms through which anti-CD-20 antibodies exert their treatment effects are controversial, but probably relate to a variety of immunological mechanisms that result in induction of tumor cell death. Treatment for more aggressive tumors often involves a combination of anti-CD-20 antibody with the conventional combination chemotherapy regimen (CHOP), which is thought to exert a synergistic effect. We will investigate the contribution that biologically specific PET imaging agents can make to evaluation of lymphoma biological activity across the entire spectrum of disease. Imaging will also be used to quantitate specific biological aspects of response to therapy. [C-11]-Thymidine PET will be used to provide quantitative data on tumor DNA synthesis. We will evaluate a new PET imaging agent for quantitating tumor cell death; [F-18]-annexin V binds to membranes that have exposed phosphatidyl serine residues resulting from programmed cell death. [C-11]-thymidine PET imaging will be used to quantitate proliferation as a sensitive agent for identifying lymphoma sites and as a growth rate baseline for quantitating response to treatment. We will use [F-18]-annexin V to quantitate tumor levels of cell death prior to, during and after treatment and we will compare the growth and death images. Image-derived tumor uptake data using these biologically specific agents will be correlated with clinical parameters used in lymphoma clinical diagnosis including histologic type, immunophenotype, Bcl-2 expression, serum LDH and beta2 microglobulin. We will use flow cytometry to quantitate the population of tumor cells in S-phase and haploid type (undergoing programmed cell death). This new imaging information will provide critical insight into treatment effectiveness through different cytotoxic mechanisms for lymphoma treatment and to design of more effective treatment strategies.
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