TRIAL AND CORRELATIVE STUDIES OF DDI IN AIDS-LYMPHOMA

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/1/917/31/95

Funding

  • National Institutes of Health: $276,928.00
  • National Institutes of Health
  • National Institutes of Health

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Lymphoma
Acquired Immunodeficiency Syndrome
Glutathione
Prochlorperazine
Clinical Trials
T-Lymphocytes
Genetic Techniques
Drug Therapy
Inborn Genetic Diseases
Anthracyclines
Viral Tumor Antigens
P-Glycoprotein
Viral Load
Reverse Transcriptase Polymerase Chain Reaction
Immunoassay
DNA Repair
Antiviral Agents
Molecular Biology
Neoplasms
Therapeutics

ASJC

  • Medicine(all)