Research
Interests:
Radiosensitization of tumors with halogenated analogs of thymidine
-
The efficacy of 5-chloro-2’-deoxyuridine as a radiosensitizer
of head and neck tumors of patients in a Phase I trial
-
The molecular mechanisms of radiosensitization by chlorodeoxycytidine
Treatment
of tumors in which hypermethylation of DNA plays a significant role
in their origin, progression, genetic instability, refractiness
to treatment or metastasis by tumor-directed hypomethylating agents
- Zebularine
as a stable, nontoxic, orally administered drug to treat tumors
in which hypermethylation plays a significant role
-
5-Fluorodeoxycytidine as a chemotherapeutic agent for breast and
colon cancer-generating 5-fluorouracil to inhibit thymidylate
synthetase as FdUMP and FdCTP to act as a tumor selective hypomethylating
agent
A
study of enzymes of pyrimidine metabolism to develop individual
treatment strategies for cancer patients including selective rescue
of normal tissue
Dr.
Greer has made several important discoveries in the course of his
scientific career. He discovered radiosensitization by 5-halogenated
analogs of uracil. He discovered depurination, which is responsible
for aging and many human tumors. He developed the principles for
selective chemotherapy of herpes virus. It was in his laboratory
that the broad specificity of the herpes thymidine kinase was first
demonstrated. He discovered suppression by derepression of an enzyme
because the enzyme had a secondary activity, which, when elevated,
could compensate for the loss of activity by mutation of an essential
enzyme. Both enzymes had a similar mechanism of activity and both
were related in the evolution of the biochemical pathway. He discovered
a phage in pathogenic bacteria, which could only be demonstrated
by electron microscopic analysis. He made the discovery that 5-methylcycitidine
could not be incorporated into DNA by the salvage pathway because
of the high Kms of dCMP kinase with respect to CH3dCMP and because
of the high activities of cytidine- and dCMP-deaminase. He has developed
a radiosensitizer, which results in 80% cures of advanced mouse
breast tumors without morbidity. Dr. Greer has spent most of his
scientific life working with 5-halogenated pyrimidine analogs.
Research
Group:
Dr.
Greer has mentored 14 graduate students toward the Ph.D. degree.
All are actively engaged in Research or Academic Medicine. Included
is Geoffrey Cooper, Professor at Harvard, now Chairman of Biology
at Boston College; Daniel Vapnek, Director of Research at AMGEN;
Ira Schildkraut, Director of Research at New England Biological
Laboratories; Karl Frank, Research Investigator at Hoffman LaRoche;
Larry Fox, Research Investigator with Anthony Fauci at the NIH;
and more recently, David Boothman, Chaired Professor, Case Western
Reserve. Dr. Greer’s students went on to postdoctoral positions
with Nobel Laureates Howard Temin and Ernst Chain and to the prestigious
laboratories of Edward Adelberg at Yale; Arthur Pardee and John
Little at Harvard; Y.C. Cheng at the University of North Carolina;
Phillip Hanawalt and Kendric Smith at Stanford, Maurice Fox at MIT
and Abner Notkins at the NIH.
Selected
Publications:
Greer,
S., Alvarez, M., Mas, M., Wozniak, C., Arnold, D., Knapinska, A.,
Norris, C., Burk, R., Aller, A., and Dauphinée, M. Five-chlorodeoxycytidine,
a Tumor-selective Enzyme Driven Radio-sensitizer, Effectively Controls
Five Advanced Human Tumors in Nude Mice. Int. J. Rad. Oncol.Biol.Phys.51:
791-806 (2001).
Cheng, J., Matsen, C., Gonzalez, F., Greer, S.,
Marquez, V., Jones, P., Selker, E. A novel inhibitor of DNA methylation,
Zebularine, can reactivate silenced genes in human cancer cells.
Accepted for Publication JNCI, November 2002.
Greer,
S., Wozniak, C., Arnold, D., Thurer, R., Agarwal, R., and Mian,
A. Pyrimidine metabolizing enzyme-driven cancer chemotherapy, radiation
therapy, and selective rescue. Miami Nature Biotechnology Winter
Symposium 2003, Volume 14, Accepted for Publication November 2002.
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