SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M
which included two prostatic tumors, three head
and neck tumors, a glioblastoma, a lung tumor,
and a breast tumor.
Cytochlor has resulted in a three-fold dose
increase effect, meaning that a dose of 70 Gy is
equivalent to a dose of 210 Gy to the tumor
without damage to underlying tissue. The success
of the radiosensitizer can be understood in view
of several biochemical studies that show: 1) 99
percent of the cells of a human prostate tumor
and a head and neck tumor incorporated the
radiosensitizer into DNA, 2) 40 percent of thymine
was replaced by 5-chlorouracil in DNA of
tumor cells, 3) all tumors obtained from patients
with head and neck tumors had elevated levels
over that of normal tissue of one of the two enzymes,
which anabolize cytochlor to become a
radiosensitizer, and 50 percent of patients had
elevations of both enzymes (averaging greater
than 10-fold), 4) 5-chlorouracil derived from
cytochlor is not removed from DNA as is 5-
iodoruacil (the first generation radiosensitizer), 5)
5-CldUMP derived from cytochlor inhibits
thymidylate synthetase as effectively as
FdUMP—this prevents the formation of TTP,
the competitor to the incorporation of CldUTP,
and 6) CldUTP activates dendritic cell (DC)
kinase, the enzyme responsible for the first step
in the anabolism of cytochlor.
Studies commissioned by the NCI have
shown that cytochlor did not display any clinical
signs of toxicity to primates when given the drug
five days per week for three weeks. No toxicity
was seen in mice and dogs where it was shown
that H 4
U extended the half life and increased the
selectivity of cytochlor. The drug is awaiting IND
approval by the FDA and will be tested in a phase
I clinical trial at UM/Sylvester in patients with
squamous cell carcinoma (SCCA) of the oropharynx
and oral cavity.
Dr. Greer also has discovered an approach to
tumors that arise or are successful as a result of
gene silencing. These include tumors due to the
silencing of genes, encoding tumor suppressor
genes, repair enzymes, migration suppressor glycoproteins
such as cadherin, estrogen receptors,
enzymes protecting cells, oxidative damage, antiangiogenesis
factors, and factors that prevent the
tumors from being controlled by the patient’s
immune system. The drug, called zebularine, can
be administered orally and is non-toxic. The NCI
has ordered the development of this drug after
studies in nude mice showed its effectiveness.
The drug also has the potential to be utilized in
patients with abnormal globin gene expression
(hemoglobinopathies) and abnormalities in the
immune system.
SELECTED PUBLICATIONS
2003
Cheng, JC, Matsen, CB, Gonzales, FA, Ye, W,
Greer, S, Marquez, VE, Jones, PA, and Selker,
EU. Inhibition of DNA methylation and reactivation
of silenced genes by zebularine. Journal of
the National Cancer Institute March 5; 95:399-
409, 2003.
HIGHLIGHTS/DISCOVERIES
• Developed and tested cytochlor, in collaboration
with the NCI, which is now under review
by the FDA for clinical application and testing.
• Developed zebularine in cooperative studies
including the University of Oregon, the University
of Southern California, the NIH, and the
University of Miami. Zebularine is approved for
further development by the NIH.
• Developed an approach for chemotherapy or
radiation therapy based on the enzymatic profile
of human tumors and adjacent normal tissue
with respect to four enzymes involved in
nucleic acid metabolism. The study requires a
small amount of biopsy material. The approach
is novel in that it involves several (nine) antimetabolites
including cytochlor and zebularine,
which have never been used in humans. The
novel approach also involves gene therapy combined
with radiation therapy, allowing greater
selectivity than gene therapy combined with
chemotherapy because of the very nature of
external beam radiation therapy.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004