SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

V I R A L O N C O L O G Y P R O G R A M
trial. His data demonstrate that IFN α potently
induces the death receptor ligand TRAIL. AZT
is phosphorylated by the herpes virus thymidine
kinase and acts by blocking NF-κB (p50, p65)
translocation into the nucleus allowing for an
unopposed death signal. AZT also down-regulates
the expression of anti-viral, anti-apoptotic
proteins such as vFLIP. A similar mechanism
has been shown to occur in other viral-induced
tumors such as post-transplant lymphoma
(EBV). Dr. Harrington and his colleagues have
initiated a new clinical trial for HHV-8-associated
lymphomas that utilizes parenteral AZT
and IFN α (these tumors virtually are always
fatal). The first patient enrolled has remained in
complete remission for more than two years.
AZT-mediated blockade of NF-κB is a potentially
exciting novel strategy that combines both
anti-HIV and EBV activity. The target malignancy
(and one of the most common worldwide)
for this type of approach is endemic
Burkitt’s lymphoma. Current studies focus on
understanding the specificity of this therapy for
herpes virus-associated lymphomas, the development
of more potent antiviral antilymphoma
thymidine analogues, and the extension of this
approach to other gamma herpes and lymphomas
that occur in the immunocompromised
patients (post-transplant, hereditary immunodeficiencies).
This work is done in collaboration
with Abdul M. Mian, Ph.D., and Ram Agarwal,
Ph.D. Dr. Harrington also recently received a
NCI-funded career award (K24), which will
enable him to focus on the above described
laboratory and clinical studies.
• Antero G. So, M.D., Ph.D., and Kathleen M.
Downey, Ph.D., recently have identified a novel
protein, polymerase delta interacting protein
(PDIP1). This protein interacts with the small
subunit (p50) of DNA polymerase delta (the
primary polymerase responsible for cell growth
and differentiation) and the proliferating cell
nuclear antigen (PCNA). PDIP1 colocalizes
with pol delta and PCNA at replication foci in
the nuclei of S-phase cells and stimulates its
activity (in the presence of PCNA). The expression
of PDIP1 can be induced by the cytokines
tumor necrosis factor alpha (TNF-α) and IL-6.
PDIP1 is a distal target of IL-6. There is increasing
evidence suggesting that the cytokine
IL-6 plays an important role in the pathogenesis
of certain types of AIDS-related lymphomas.
Recent studies strongly have implicated a critical
role for IL-6 in EBV-dependent lymphoproliferative
disease. It also has been reported
that the development of AIDS-associated
Burkitt’s/small non-cleaved cell lymphoma is
preceded by elevated serum levels of IL-6. In
addition, cell lines derived from HHV-8-associated
AIDS primary effusion lymphomas constitutively
secrete high levels of both IL-6 and the
HHV-8 IL-6 homologue (vIL-6). Consistent
with these findings is the observation that the
inhibition of NF-κB (by AZT or other inhibitors)
down-regulates cytokine IL-6 and induces
apoptosis in Karposi’s sarcoma-associated herpes
virus (KSHV) infected cells.
• Researchers in Lawrence H. Boise, Ph.D.’s laboratory
investigate factors that regulate the pathways
associated with death receptor-induced
apoptosis. Previous studies have indicated that
cells can utilize one of two pathways to propagate
death signals resulting from the ligation of
the TNF receptor as well as from CD95 (Fas/
Apo-1). Cells referred to as type I cells can activate
a caspase cascade that does not require release
of factors from the mitochondria.
Expression of anti-apoptotic proteins Bcl-2 or
Bcl-x L
is incapable of inhibiting death receptor
signaling in type I cells. In contrast, death receptor
signaling in type II cells requires release
of mitochondrial factors and is inhibited by
Bcl-2/x L
expression. Dr. Boise has demonstrated
that cells can utilize both type I and type II signals
and that Bcl-2/x L
can affect type I death
receptor signaling when used in concert with
inhibitors of signaling caspases. Interestingly, γ-
herpes viruses associated with Karposi’s sarcoma
and PELs encode both a Bcl-2 homologue as
well as an inhibitor of CD95 signaling (vFlip).
While it has been previously suggested that viruses
express these molecules to block distinct
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 131