TUMOR-DNA DIRECTED THERAPY WITH NOVEL FLUOROPYRIMIDINES

  • Greer, Sheldon, (PI)

Project: Research project

Description

5-Fluorodeoxycytidine (FdC) and 5-trifluoromethyldeoxycytidine
(F3methyldC), each coadministered with tetrahydrouridine (H4U), an
inhibitor of cytidine deaminase (CD) are far superior to 5-fluorouracil
(FUra), 5-fluorodeoxyuridine (FdU) and 5-trifluorothymidine (F3dT) in the
two mouse tumor models tested, Lewis lung carcinoma and mammary
adenocarcinoma-755. These prodrugs are activated by different enzymes than
fluoropyrimidines currently used and unlike them, are resistant to
catabolism. FdC and F3methyldC are preferentially converted in tumor to
toxic nucleotides by enzymes elevated in human malignant tumors for
example, dCMP deaminase is elevated 20- to 80-X in many human tumors. Due
to the high CD levels in tumor, the use of moderate doses of H4U allows
dual pathway activation of FdC specifically in tumors so that RNA-directed
antimetabolites (FUMP) are formed to a very great extent and incorporated
into RNA of tumor with little or no formation or incorporation in normal
tissue, including bone marrow and intestine. Utilizing FdC + H4U, RNA
level antimetabolite pools, FdU and FdUMP are generally greater than
100-fold lower in normal tissues than in tumor. In contrast, the use of
FdU or FUra results in higher levels (greater than 30-fold) of DNA and
RNA-directed metabolites in normal tissues and with FdU, lower levels (less
than 1/20) of FdUMP, the inhibitor of thymidylate synthetase (TS), in tumor
tissue than when FdC + H4U is utilized. Incorporation of analogs into
nucleic acids also shows increased selectivity of FdC + H4U over FdU and
FUra. The selectivity of F3methyldC is also based on moderate doses of H4U
amplifying intrinsic differences between levels of CD in tumor and normal
tissues. 3H-FdC and 14C-F3methyldC metabolism and pharmacokinetic will be
studied. We will determine, in normal and tumor tissue, to what extent:
a) human surgical tissue specimens and human tumor cell lines contain
elevated levels of the relevant enzymes. In this manner we will confirm
studies of others indicating that the most frequently occurring human
malignant tumors (of colon, breast, lung, rectum and brain) and many human
leukemias possess high levels of an enzyme(s) essential for response to our
strategy, b) a limited number of human tumor cell lines display sensitivity
to these dC analogs with or without H4U or dH4U, c) F3methyldCMP and
F3thymine are formed in metabolite studies similar to those we have
completed with adenocarcinoma-755 and Lewis lung carcinoma, d) FdUMP and
F3dTMP are formed and retained, e) normal metabolite pools are affected, f)
DNA synthesis and TS activity and their recovery are affected, g)
F3methyldC and its metabolites are incorporated into DNA, h) FdC (and
F3methyldC) incorporation affects 5-methyldC/dC ratios in DNA; that is, to
what extent is DNA hypomethylated under conditions of therapy.
StatusFinished
Effective start/end date1/1/8712/31/89

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Genetic Therapy
Floxuridine
Fluorodeoxyuridylate
Neoplasms
Cytidine Deaminase
DNA
Lewis Lung Carcinoma
Thymidylate Synthase
Enzymes
Tumor Cell Line
Fluorouracil
Tetrahydrouridine
Trifluridine
RNA
Antimetabolites
Prodrugs
Rectum
Intestines
Colon
Adenocarcinoma

ASJC

  • Medicine(all)