The long term objectives of this proposal are to devise more effective treatment of AIDS-lymphomas and to more precisely characterize the molecular and genetic characteristics of this disease. This will be accomplished by interdisciplinary clinical and basic research studies at the University of Miami and in the context of the AIDS-Lymphoma Network.
The specific aims at this institution are: 1) An innovative clinical trial combining retroviral and antitumor therapy has been developed. A phase I followed by a phase II study of dideoxyinosine (ddI) in conjunction with standard but appropriately modified lymphoma chemotherapy will be carried out. DdI was chosen for its antiviral effectiveness and non myelosuppressive toxicity profile. The lymphoma chemotherapy was also designed to avoid overlapping toxicity profiles as much as possible. 2) Lymphoma specimens will be obtained for correlative laboratory studies within this institution and for other studies within the AIDS-Lymphoma Network. A hematopathology tumor bank and the procedures for obtaining, preserving and transporting tissues have been established. Specimens will be characterized pathologically according to the working formulation; phenotypically by an extensive panel of antibodies against B and T cell antigens and genotypically by molecular genetic techniques. 3) Correlation studies of immune composition lymphocyte subsets determined by two and three color fluorescence, T cell function and natural killer cell activity determined in proliferation and cytotoxicity assays, and the relative levels of known components of the lymphokine/cytokine network and some cytoplasmic signal transduction proteins. Gene expression will be measured at both the mRNA and protein levels using reverse transcriptase coupled polymerase chain reaction and solid phase immunoassays respectively) and viral burden (p24 antigen and B-microglobulin) will be performed before, during and after treatment. This data will provide insight into the cellular basis of retroviral- associated lymphomagenesis and will allow assessment of the effectiveness of the treatment in terms of immune compromise and viral infection. It will also define the prognostic value of several immunological parameters. 4) Correlative studies of tumor response and in vitro resistance to chemotherapy and radiation will be performed. P-glycoprotein expression, glutathione synthesis and DNA repair will be measured. P- glycoprotein will be measured by a series of monoclonal antibodies and flow cytometry. In addition, anthracycline retention within tumor cells and its modulation by prochlorperazine (an anti-P-glycoprotein agent) will be studied. Glutathione levels and related enzymes will be assayed using fluorometric and flow cytometric methods. DNA repair will be studied using the alkaline unwinding techniques. This information will assist in the design of subsequent clinical trials of enhanced therapeutic effectiveness.
