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Potential therapeutic
indications
Leukaemia.
Proposed therapeutic
intervention
Oligodeoxynucleotides (ODNs).
Research site
Telephone number
Fax number
Email address
Epstein@nso1.uchc.edu
Website address
www.uchc.edu
Author
Paul M Epstein
This work is currently supported by a research grant from the Robert Leet
and Clara Guthrie Patterson Trust, Fleet Bank, Trustee. There are no
associated licensing restrictions or exertion of intellectual rights by the
granting agency, over discoveries made through the support of this grant.
Background
It is estimated that by the end of this year, 27,600 new cases of leukaemia
will be diagnosed, and 21,000 deaths will result this year from this disease.
While chemotherapy regimens are effective in inducing remission in many
cases, these are harsh treatments, and it has been found that 80% of adult
patients eventually relapse and die of the disease [1]. Hence, new and
effective treatments for leukaemia are therefore needed.
Inhibition ofEndocrine
Oncologic,
calcium-calmodulin
& Metabolic
dependent phosphodiesterase
[1]. BRAUN SE et al.: Gene therapy strategies for leukemia. Mol. Med. Today (1997)
3:39-46.
One novel approach that avoids harsh chemotherapeutic agents is the use
of antisense to block the expression of specific genes that would curtail the
growth or induce the death of the leukaemic cell. Antisense
oligodeoxynucleotides (AS ODNs) targeted to a number of oncogenes, such
as c-myc, c-myb, and c-raf, have all been shown to block proliferation and/or
induce apoptosis in leukaemic cells in vitro, or in severe combined
immunodeficient (SCID) mouse models of human leukaemia [1].
In our laboratory, we have cloned the cDNA for a form of Ca2+-calmodulin
dependent PDE1B1, from human leukaemic cells, which regulates levels of
the signalling molecule, cAMP [2]. We showed that PDE1B1 is expressed
only in activated and transformed lymphocytes, but not in normal, resting
lymphocytes. Moreover, PDE1B1 expression is restricted to proliferating
lymphocytes and to regions of the brain, and does not appear to be
109
1998 Ashley Publications Ltd. ISSN 1460-0412
Biologicals in house
Tools available
Cultured human leukaemic cell lines, cloned cDNA for human PDE1B1, AS
ODNs targeted to PDE1B1, reverse transcription polymerase chain reaction
(RT-PCR) strategies to determine the expression of the mRNA for subtypes of
PDE1 and PDE4, assays for the measurement and detection of PDE gene
families.
Collaborative research
envisaged
Multinational pharmaceutical
company
Other