[Federal Register Volume 68, Number 122 (Wednesday, June 25, 2003)]
[Notices]
[Pages 37852-37853]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-15972]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by agencies of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Oligodeoxyribonucleotides Comprising O6-Benzylguanine and 
Their Use

Robert Moschel et al. (NCI)
U.S. Patent 6,060,458 issued 09 May 2000,
Licensing Contact: George Pipia; 301/435-5560; [email protected].
    The DNA repair protein, O6-alkylguanine-DNA 
alkyltransferase (alkyltransferase) is the primary source of tumor cell 
resistance to alkylating chemotherapeutic drugs that modify the 
O6-position of DNA guanine residues. Inactivators of 
alkyltransferase are currently in use to enhance chemotherapy by these 
alkylating drugs. The prototype inactivator, O6-
benzylguanine is currently in Phase II and III clinical trials as an 
adjuvant to improve chemotherapy. Although O6-benzylguanine 
is a promising inactivator, it is not an ideal drug since it is only 
sparingly soluble in water and it is not effective in inactivating some 
mutant alkyltransferase proteins that could possibly be produced after 
repeated chemotherapy cycles.
    Oligodeoxyribonucleotides containing O6-benzylguanine 
residues represent another class of alkyltransferase inactivators. They 
are extremely water soluble alkyltransferase inactivators that can 
efficiently inactivate the alkyltransferase protein at much lower 
concentrations than O6-benzylguanine. In addition, 
oligodeoxyribonucleotides containing O6-benzylguanine are 
effective in activating several mutant alkyltransferase proteins that 
are highly resistant to inactivation by O6-benzylguanine. 
For example, oligodeoxyribonucleotides between 7 and 11 nucleotides in 
length containing multiple O6-benzylguanines are effective 
in inactivating several alkyltransferase molecules per oligonucleotide 
molecule at 300 fold lower concentrations than O6-
benzylguanine. These same substrates are also effective inactivators of 
mutant alkyltransferase molecules that are resistant to inactivation by 
O6-benzylguanine. In addition, positioning O6-
benzylguanine near the 3'-or 5'-terminus of these 
oligodeoxyribonucleotides improves their resistance to degradation by 
cellular nuclease proteins. Therefore, oligodeoxyribonucleotides 
containing multiple O6-benzylguanine residues may be more 
effective chemotherapy adjuvants than O6-benzylguanine as 
the free base.

Imidazoacridones with Anti-Tumor Activity

Christophe Michejda et al. (NCI) DHHS Reference No. E-289-1999 (and 
related U.S. and foreign patents/applications) and U.S. Patent 
6,541,483 issued 01 April 2002 (and related U.S. and foreign patents/
applications),
Licensing Contact: George Pipia; 301/435-5560; [email protected].
    The present invention relates to novel bifunctional molecules with 
anti-tumor activity. These agents are composed of an imidazoacridone 
moiety linked by a nitrogen containing aliphatic chain of various 
length and rigidity to another aromatic ring system capable of 
intercalation to DNA.

[[Page 37853]]

    Previous studies on related symmetrical bis-imidazoacridones 
revealed that only one planar imidazoacridone moiety intercalates into 
DNA. The second aromatic moiety, which is crucial for biological 
activity, along with the linker resides in DNA minor groove, and is 
believed to interact with DNA-binding proteins (most likely, 
transcription factors and /or repair proteins). The symmetrical bis-
imidazoacridones arrest the growth of sensitive cancers (especially 
colon cancers) but do not kill the tumors. It was hypothesized that the 
growth arrest was due to the inability of the affected tumor cells to 
repair DNA damage caused by the compounds. Remarkably, bis-
imidazoacridones are very well tolerated, are very tissue selective and 
do not appear to damage normal tissues.
    Since the binding of the symmetrical bis-imidazoacridones to DNA 
was unsymmetrical, the inventors have developed unsymmetrical compounds 
in which one imidazoacridone moieties was replaced by other 
intercalating groups, with the expectation that this would enhance 
biological activity while retaining the remarkable tissue selectivity 
and low systemic toxicity. The new compounds contain intercalating 
moieties such as 3-chloro-7-methoxyacridine or naphthalimide along with 
the original imidazoacridones.
    These new compounds, especially those containing naphthalimide 
moiety, are extremely cytotoxic against variety of tumor cells in vitro 
(IC50 at low nanomolar range) and kill tumor cells by inducing 
apoptosis. In vivo, in nude mice xenografted with human tumors, the 
compounds significantly inhibited the growth of such tumors as colon 
tumor HCT116 and Colo205 as well pancreatic tumors (lines 6.03 and 
10.05 freshly established from a patient). These compounds are 
extremely potent agents against hepatocellular carcinoma as evidenced 
by their ability to eradicate liver cancer in an orthotopic liver 
cancer model in rats. The primary molecular target of these very potent 
compounds is the inhibition of both topoisomerase I and II, although 
other targets may be important as well. Remarkably, no toxicity was 
observed at the therapeutic doses. These are among the most potent 
agents known against cancers of the GI tract and appear to be tolerated 
very well.

    Dated: June 16, 2003.
Steven M. Ferguson,
Acting Director, Division of Technology Development and Transfer, 
Office of Technology Transfer, National Institutes of Health.
[FR Doc. 03-15972 Filed 6-24-03; 8:45 am]
BILLING CODE 4140-01-P