CURRICULUM VITAE
Languages: English (native); Spanish (conversant)
1962-1966. B.A. degree - the University of Vermont.
Psychology/Philosophy major.
1966-1967. Completed one year of pre-clinical study at Tufts University
School of Dental Medicine.
1967-1970. Ph.D. degree - Yale University, Dept. of Pharmacology.
Mentor - Dr. David G. Johns.
Thesis: Pyrazolo[3,4-d]pyrimidines As Substrates and Inhibitors
of Xanthine Oxidase and Aldehyde Oxidase (molecular mechanism
of allopurinol).
*Note: full Ph.D. program was completed
within 36 months.
1970-1972. Postdoctoral Fellow. University of Michigan, Dept.
of Biological Chemistry. Mentor - Dr. Vincent Massey
Field of interest: Flavoprotein Hydroxylase (first demonstration
of an oxygenated-flavin catalytic intermediate).
II. Primary Appointment
Wellcome Research Laboratories (Burroughs Wellcome)
Division of Experimental Therapy, Section of Enzymology:
1972. Senior Research Biochemist III.
1976. Senior Research Biochemist IV.
1981. Senior Research Biochemist V.
1986. Principal Scientist.
1993. Assistant Division Director and Principal Scientist.
1994. Associate Division Director and Principal Scientist.
GlaxoWellcome (now GSK)
1995. International Vice President Cancer Research
1997. Retired
Pharmaceutical Consultant
1997-present
Meditation Teacher
1976-present
click
here for Medition Web Site
University of North Carolina
Department of Pharmacology
1976--present. Adjunct Professor
1987-1990. Consultant in Enzymology to the Department of Oral Biology at The University of Michigan. Ann Arbor, Michigan.
1997- 2001. Member of the Board of Directors of Cornucopia House (provides support to cancer patients)
1998 (August). Visiting Professor at the Department of Medicine and Therapeutics at The University of Aberdeen, Aberdeen Scotland.
1999-2001. Scientific Advisory Board Member for Krenitsky Pharmaceuticals, Inc.
1999-2001. Consultant to Glaxo Wellcome (now GSK), Department of Clinical Pharmacology.
2000-present. Consultant to various pharmaceutical companies and law firms.
1976. American Society of Biological Chemistry and Microbiology.
1977. American Chemical Society.
1988. American Society Microbiology.
1993. American Association for Cancer Research.
2003. American Medical Writers Association.
VI. Professional Training (Major)
1989. A one-week intensive Leadership Development Course presented by The Center
For Creative Leadership.
1992. Burroughs Wellcome Management Institute at The Kenan-Flagler Business
School of The University of North Carolina (three to four days residency per
month for six months).
1993. LeaderLab Course. A six-month course consisting of two one-week intensive
sessions plus weekly follow-up telephone discussions. Presented by The Center
For Creative Leadership.
1995. Managing Global Networks. A three-day course for International Project
Leaders.
2004. The Legacy Center: Basic and Advanced Leadership Courses
2006. The Legacy Center: Masters Leadership Course
1965-1966. National Science Foundation Student Fellowship for
Research in Psychology.
1967-1970. National Science Foundation Graduate Student Fellowship.
1970-1972. Recipient of the Jane Coffin Childs Memorial Fund for
Medical Research Postdoctoral Fellowship.
VIII. Fields of Interest
Burroughs Wellcome 1972 to 1995
Research
My primary interest involved drug interactions with chemotherapeutically important enzymes. The research generally probes the enzymes' mechanism as a basis to understand and design active agents. I have been particularly interested in tight-binding or inactivating enzyme inhibitors.
Major research efforts have involved studies of enzymes from human viruses and human tissues. These studies have unraveled the mechanisms of actions of several active chemotherapeutic agents and have been instrumental in the design of novel lead compounds with exciting activities. Other findings have revealed unexpected aspects of certain inhibitors that have fostered strategies for their use in novel areas. We also discovered two enzyme inactivators that potentiate the activity of two different therapeutic agents.
Studies directed towards antiviral and antitumor chemotherapy, cholesterol lowering, and nitric oxide-related diseases were in progress in 1995.
Drug Discovery and Development
I spent the majority of my time on drug discovery and development. I have enjoyed the simultaneous roles of Project Leader on a contemporary project and of research coordinator to advance the next compound to project status. The following discoveries were derived from personal initiatives. Patents were filed and the active compounds were developed as candidate drugs to the extent indicated below.
Active Project (Eniluracil)
Eniluracil (776C85), a potentiator of the antitumor activity of 5-fluorouracil (5-FU): Eniluracil, (5-ethynyluracil) inactivates uracil reductase (DPD), the enzyme that rapidly degrades 5-FU in cancer patients. Eniluracil thereby improves the efficacy, the therapeutic index, and the oral bioavailability of 5-FU in laboratory animals. A project was formed to develop this combination therapy (Cytefuran®) for treatment of solid tumors. Clinical trials started in May 1994. I was the International Project Leader for the preclinical and eight months of Phase I clinical development stages. Initial clinical results are very promising. I remained active in this project until retirement and continued as a consultant thrugh 2001. In 2004, I discovered the proper method to administer eniluracil and 5-FU and filed a patent in conjunction with Adherex Technologies, Inc. I am currently supporting their development of eniluracil .
Inactive Major Projects
348U87, a potentiator of the antiviral efficacy of acyclovir: 348U87 is an inactivator of herpes ribonucleotide reductase that synergizes with acyclovir against wild type and acyclovir-resistant herpes simplex types I and II and varicella zoster viruses. I was Project Leader to develop this topical therapy from its inception through the IND submission in 1990 for pilot studies. A clinical trial for herpes labialis ending in August 1994 was negative. Additional trials are not being pursued.
776C85, an inactivator of uracil reductase that protects mice from the hematological toxicity of AZT (Retrovir): 776C85 inactivated uracil reductase and significantly ameliorated the anemia induced by AZT in mice and dogs. However, our interest in developing this drug further was tempered by its lack of protection in monkeys.
Oxypurinol, an inhibitor of xanthine oxidase that protects ischemic tissues from reperfusion injury: The finding that oxypurinol could rapidly inhibit the generation of superoxide radicals from xanthine oxidase even in the presence of high concentrations of physiological substrates led to patent filings and the formation of a Project Team for drug development. A patent for the synergistic use of oxypurinol and tissue plasminogen activator (TPA) was also filed. Although initial studies in dogs showed significant cardiac protection by oxypurinol, later studies were less convincing and the Project was discontinued.
Analogs to lower LDL cholesterol: We have a compound that lowers LDL cholesterol by 50% and raises HDL cholesterol by 100% in monkeys. A formal program had been formed to determine the usefulness of this agent, but was discontinued after the Glaxo-Wellcome integration.
Principal Scientist
The position of Principal Scientist is the highest scientific
(nonadministrative) position at Burroughs Wellcome Co. There are
approximately two Principal Scientists in each Division. The responsibilities
entail consultations on divisional and company-wide matters, such
as scientific reviews and directions, interviewing candidates,
and scientific leadership. They also include establishing collaborations
with external investigators and international concerns.
Associate Division Director
This position expanded the scientific leadership role within our division of 60 scientists and added significant administrative responsibility in the Division of Experimental Therapy. The Division contained departments of Enzymology, Metaboloic Studies, Chemistry (organic and enzyme-catalyzed synthesis), Cell Biology/Virology, and Immunology.
Teaching and Consulting
A significant teaching responsibility to the Department of Pharmacology at the University of North Carolina and The University of Michigan included lectures, tutorials, thesis committee membership and supervising Postdoctoral and Predoctoral students. I also provided scientific consultations and lectures for The University of Michigan and Aberdeen University (Scotland).
Glaxo Wellcome 1995 to 1997
Responsibilities
As International Vice President Cancer Research, I was chairman of the Cancer Therapeutic Research Committee, which oversees the progress of Cancer Research Projects as leads are optimized. We worked closely with Development, Clinical, and Commercial to ensure that the end products are useful. I also co-chaired the International Oncology Strategic Team and attended regular International Therapeutic Directors Meetings that were concerned with cross-therapeutic issues. I continued to represent Research on the 776C85 Product Development Team.
IX. Major Committees and Service
1973-1995. Emergency Medical Response Team
1976-Present. Ph.D. Thesis Committee; Univ. North Carolina, Dept.
Pharmacology.
1977. Organized "The Applications of Enzyme Kinetics"
lecture series.
1980-1992. Designed and taught a course at Burroughs Wellcome
that uses meditation techniques for stress reduction and relaxation.click here
for Meditation Web Site
1985-1989. Project Member of Q-19 for Treatment for Oxygen Toxicity
1985-1987. Preproject Leader and Originator of V-14 (Antiviral
Combination Therapy: 1110U81/Acyclovir)
1986. Leader of a committee to evaluate Df1 for prevention
of oxygen toxicity.
1986-1987. Project member P57 (use of oxypurinol to prevent
reperfusion injury).
1987-1988. Project Leader and Originator of P58 (Antiviral
Combination Therapy Drug Development: 1110U81/Acyclovir).
1988-1990. Project Leader and Originator of P61 (Antiviral
Combination Therapy Drug Development: 348U87/Acyclovir). IND filed
in 1990.
1991-1994. Continued Project Membership (post IND) on Project P61 (renamed P120).
1989-1991. Site coordinator for international HIV-Protease
drug development program.
1990-1991. Research representative to a committee to evaluate
and implement scientific writing courses at Burroughs Wellcome.
1990-1993. Experimental Therapy's international representative
for nitric oxide research.
1992. Research representative to Employee Involvement Committee.
1992-1994. International Project Leader and originator (preclinical
and Phase I clinical stages) of P146 (Combination Antitumor Therapy
Drug Development: 776C85/5-fluorouracil).
1995-1997. Project member of P146 (Combination Antitumor Therapy
Drug Development: 776C85/5-fluorouracil).
1992-1995. RDM representative to describe our process for drug
discovery and development at new employee orientations.
1994-1995. Program 20R (program to develop new lead for cholesterol-lowering)
Member and originator.
1995. Vice Chairman: Purines Pyrimidnies and Related Substances,
Gordon Research Conference. Newport, Rhode Island
_________________________
1995. Member of the Executative Glaxo Wellcome Research Integration
Team
________________________
1995-1997. Chairman of Cancer Therapeutic Research Committee,
which oversees the progress of Research Projects as leads are
optimized..
1995-1997. Co-Chairman of the Oncology Therapeutic Strategy
Team, which is responsible for area and disease reviews and for
overseeing the partnership between Research, Development, Clinical,
and Commercial.
1995-1997. Member of the International Therapeutic Research
Committee, which coordinates research across the therapeutic areas.
1995-1997. Member of the US Research Committee
1995-1997. Member of the US Research Targets Committee
1995-1997. Continued project membership on the 776C85 enhancer
of 5-fluoracil 'top priority' treatment for solid tumors (see
above).
1995-1997. Core Team Member of the Cancer Research Forum
1995-1997. Licensing Opportunity Evaluation Team Member
________________________
1997- present . Volunteer fot the Duke Comprehensive Cancer Center Patient Support
Program
1997. Session Chairman for Anticancer and Antiviral Agents:
Purines Pyrimidnies and Related Substances, Gordon Research Conference.
Newport, Rhode Island
X. Invited Seminars
1. September 14, 1972. Burroughs Wellcome, Dept. Experimental
Therapy. "para-Hydroxybenzoate Hydroxylase from Pseudomonas
Fluorescens: Studies with a Flavoprotein"
2. May 9, 1975. Duke University, Dept. Biochemistry. "Kinetic
Studies with GMP Synthetase: Product-Dependent Inhibition by Nucleosides"
3. March 30, 1975. Fifth International Symposium on Flavins
and Flavoproteins. (Invitation declined)
4. June 4, 1979. University of South Florida, Dept. Biochemistry.
"Slow-Binding and Tight-Binding Inhibitors of Adenosine Deaminase"
5. July 20, 1979. University of Vermont, Dept. Pharmacology.
"Slow-Binding and Tight-Binding Inhibitors of Adenosine Deaminase"
6. October 15, 1981. State University of New York (Syracuse),
Department of Pharmacology. "Exploitable Differences Between
Host and Protozoal Nucleotide Interconverting Enzymes"
7. November 2, 1981. University of North Carolina, Cancer Research
Center. "Exploitable Differences Between Host and Protozoal
Nucleotide Interconverting Enzymes"
8. July 17, 1984. University of Connecticut, Department of
Infectious Disease. "Mechanism of Acyclovir's Anti-Herpetic
Activity"
9. October 11, 1985. American Society of Microbiology. Regional
Meeting Greensboro, N.C. "Potentiation of Acyclovir's Antiherpetic
Activity by Inhibition of Ribonucleotide Reductase"
10. November 19, 1985. Bowman Gray School of Medicine, Dept.
Biochemistry. "Potentiation of the Antiherpetic Activity
of Acyclovir"
11. April 23, 1986. University of Michigan, Department Oral
Biology. "Potentiation of Acyclovir by Inhibition of Ribonucleotide
Reductase"
12. July 25, 1986. Gordon Research Conference. Plymouth New
Hampshire. "Potentiation of Acyclovir by Inhibition of Ribonucleotide
Reductase"
13. July 28, 1986. Wellcome International Conference on Antiviral
Drug Design. North Hampton, U.K. "Synergistic Antiviral Chemotherapy"
14. February 2, 1987. University of Nevada, Department of Biochemistry.
"Potentiation of Acyclovir by Inhibition of Herpes Ribonucleotide
Reductase"
15. February 12, 1987. Gordon Research Conference, Santa Barbara,
California. "Inhibitor of Xanthine Oxidase Catalyzed Production
of Superoxide Anion" (invitation declined)
16. March 25, 1987. Triangle Virology Society, Raleigh, North
Carolina. "Potentiation of Acyclovir by Inhibition of Herpes
Ribonucleotide Reductase"
17. August 3, 1987. Gordon Research Conference, New London,
New Hampshire. "Potentiation of Acyclovir by Inhibition of
Herpes Ribonucleotide Reductase"
18. July 6, 1988. Symposium on Metabolic Aspects of Chemotherapy. Gdansk, Poland "Ribonucleotide Reductase as A Target For Antiviral Chemotherapy" (invitation declined)
19. Oct. 4-6, 1988. Univ. of Michigan. Three lecture series
on "Unusual Inhibitors of DNA Synthesis"
20. July 10, 1988. Gordon Research Conference, Newport, Rhode
Island. "Synergistic Anti-Herpetic Therapy: Mechanism Studies"
21. January 25, 1990. Emory University School of Medicine,
Department of Biological Chemistry. "Potentiation of Acyclovir
by Inhibition of Herpes Ribonucleotide Reductase"
22. December 3, 1990. University of Delaware, Department of
Chemistry and Biochemistry. "Potentiation of Acyclovir by
Inactivation of Herpes Ribonucleotide Reductase".
23. June 19, 1991. The Third International Symposium on Molecular
Aspects of Chemotherapy. Gdansk, Poland. "Potentiation of
Acyclovir by Inhibition of Herpes Ribonucleotide Reductase"
(invitation declined).
24. June 17, 1992. The 17th Northwest Regional American Chemical
Society Meeting. The University of Montana. "BW 348U87: an
Inactivator of Herpes Ribonucleotide Reductase That Potentiates
Acyclovir ".
25. Sept. 17, 1992. Tenth International Roundtable: Nucleosides,
Nucleotides and Their Biological Applications, Park City Utah.
"Inactivators and Apparent Inactivators of Purine and Pyrimidine
Metabolizing Enzymes".
26. July 5, 1993. Gordon Research Conference, Newport, Rhode
Island. "5-Ethynyluracil: An Inactivator Of Uracil Reductase
That Potentiates The Antitumor Activity Of 5-Fluorouracil".
27. March 30, 1995, University of Texas Health Science Center
at San Antonio "776C85: A New Modulator Of The Antitumor
Activity Of 5-Fluorouracil".
28. June 5, 1995, Memorial Sloan-Kettering Cancer Center "Modulation
of 5-Fluorouracil by 776C85: From Biochemistry to Phase I".
29. July 5, 1995. Gordon Research Conference, Newport, Rhode
Island. "5-Ethynyluracil (776C85)/5-Fluorouracil: Preclinical
and Clinical Studies".
30. May 23, 1996. University of Chicago Medical Center. "5-Ethynyluracil
(776C85): A New Modulator of 5-Fluorouracil".
_________________________________________
31. Nov. 19, 1997. Duke Comprehensive Cancer Center Patient
Support Program. "Trends in Cancer Research"
32. August 12, 1998. Aberdeen University (Scotland) "5-Ethynyluracil:
A Modulator of 5-Fluorouracil Antitumor Activity". Plus four
informal seminars.
XI. Bibliography (Full-Length Manuscripts)
1. Spector, T. and Johns, D.G. "Oxidation of 4-Hydroxypyrazolo [3,4-d]pyrimidine by Xanthine Oxidase: The Route of Electron Transfer From Substrate to Acceptor Dyes." Biochem. Biophys. Res. Communs. 32, 1039-1044 (1968).
2. Johns, D.G., Spector, T., and Robins, R.K. "Studies on the Mode of Oxidation of Pyrazolo[3,4-d]pyrimidine by Aldehyde Oxidase and Xanthine Oxidase." Biochem. Pharm. 18, 2371-2383 (1969).
3. Spector, T. and Johns, D.G. "4- Hydroxypyrazolo[3,4-d]pyrimidine as a Substrate For Xanthine Oxidase: Loss of Conventional Substrate Activity with Catalytic Cycling of the Enzyme." Biochem. Biophys. Res. Communs. 38, 583-589 (1970).
4. Spector, T. and Johns, D.G. "Stoichiometric Inhibition of Reduced Xanthine Oxidase by Hydroxypyrazolo[3,4-d]pyrimidines." J. Biol. Chem. 245, 5079-5085 (1970).
5. Spector, T. and Massey, V. "Interactions of Substrate and Non- substrate Effectors with p-Hydroxybenzoate Hydroxylase from Pseudomonas fluorescens." Biochem. Biophys. Res. Commun. 45, 1219-1226 (1971).
6. Howell, L.G., Spector, T., and Massey, V. "Purification and Properties of p-Hydroxybenzoate from Pseudomonas fluorescens." J. Biol. Chem. 247, 4340-4350 (1972).
7. Spector, T., and Massey, V. "Studies on The Effector Specificity of p-Hydroxybenzoate Hydroxylase from Pseudomonas fluorescens." J. Biol. Chem. 247, 4679-4687 (1972).
8. Spector, T. and Massey, V. "p-Hydroxybenzoate Hydroxylase from Pseudomonas fluorescens: Evidence for an Oxygenated Flavin Intermediate." J. Biol. Chem. 247, 5632-5636 (1972).
9. Spector, T. and Massey, V. "p-Hydroxybenzoate Hydroxylase from Pseudomonas fluorescens: Reactivity with Oxygen." J. Biol. Chem. 247, 7123-7127 (1972).
10. Spector, T., Miller, R.L., Fyfe, J.A. and Krenitsky, T.A. "GMP Synthetase from E. coli B-96: Interactions with Substrate Analogs." Biochim. Biophys. Acta, 370, 585-591 (1974).
11. Spector, T. and Beacham, L.M. III "GMP Synthetase from E. coli B-96: Inhibition by Nucleosides." J. Biol. Chem. 250, 3101-3107 (1975).
12. Spector, T. "Studies with GMP Synthetase from Ehrlich Ascites Cells: Purification, Properties, and Interactions With Nucleotide Analogs." J. Biol. Chem. 250, 7372-7376 (1975).
13. Spector, T. and Miller, R.L. "Mammalian Adenylosuccinate Synthetase: Nucleotide Monophosphate Substrates and Inhibitors." Biochim. Biophys. Acta 445, 509-517 (1976).
14. Spector, T., Jones, T.E., Krenitsky, T.A., and Harvey, R.H. "Guanosine Monophosphate Synthetase from Ehrlich Ascites Cells: Multiple Inhibition by Pyrophosphate and Nucleosides." Biochim. Biophys. Acta 452, 597-607 (1976).
15. Spector, T. "Mammalian Adenylosuccinate Lyase: Participation in the Conversion of 2'-dIMP and ß-D-Arabinosyl-IMP to Adenine Nucleotides." Biochim. Biophys. Acta 481, 741-745 (1977).
16. Spector, T. "Inhibition of Urate Production by Allopurinol." (Commentary) Biochem. Pharmacol. 26, 355-358 (1977).
17. Agarwal, R.P., Spector, T., and Parks, R.E., Jr. "Tight Binding Inhibitors: IV. Inhibition of Adenosine Deaminases by Various Inhibitors." Biochem. Pharmacol. 26, 359-367 (1977).
18. Miller, R.L., Adamczyk, D.L., and Spector, T. "Reassessment of the Interactions of Guanylate Kinase and 6-Thioguanosine 5'-Phosphate." Biochem. Pharmacol. 26, 1573-1576 (1977).
19. Spector, T. "Refinement of the Coomassie Blue Method of Protein Quantitation: A Simple and Linear Spectrophotometric Assay for 0.5-50 Micrograms of Protein." Analyt. Biochem. 86, 142-146 (1978).
20. Spector, T. "GMP Synthetase From Ehrlich Ascites Cells." in "Methods in Enzymology, Purine and Pyrimidine Nucleotide Metabolism." Vol. LI, pp. 219-224 (eds. P.A. Hofee and M. E. Jones) NY Acad. Press (1978).
21. Spector, T. "Precise Temperature Control of the Gilford Spectrophotometer: A Simple and Inexpensive Modification." Analyt. Biochem. 93, 171-173 (1979).
22. Spector, T., Jones, T.E., and Miller, R.L. "Reaction Mechanism and Specificity of Human GMP Reductase: Substrates, Inhibitors, Activators and Inactivators." J. Biol. Chem. 254, 2308-2315 (1979).
23. Spector, T., Jones, T.E., and Elion, G.B. "Specificity of Adenylosuccinate Synthetase and Adenylosuccinate Lyase from Leishmania donovani: Selective Amination of an Antiprotozoal Agent." J. Biol. Chem. 254, 8422-8426 (1979).
24. Spector, T. "Charcoal-Facilitated Dialysis." Analyt. Biochem. 103, 313-316 (1980).
25. Spector, T. and Cleland. W.W. "Meanings Of Ki For Conventional and Alternate-Substrate Inhibitors." Biochem. Pharmacol. 30, 1-7 (1981).
26. Spector, T. and Hajian, G. "Statistical Methods to Distinguish Competitive, Noncompetitive and Uncompetitive Enzyme Inhibitors." Analytical Biochem. 115, 403-409 (1981).
27. Marr, J.J., Berens, R.L., Nelson, D.J., Krenitsky, T.A., Spector, T., LaFon, S.W., and Elion, G.B. "Antileishmanial Action of 4-Thiopyrazolo[3,4-d]pyrimidine and Its Riboside: Biological Effects and Metabolism." Biochem. Pharmacol. 31, 143-148 (1982).
28. Spector, T., Berens, R.L., and Marr, J.J. "Adenylosuccinate Synthetase and Adenylosuccinate Lyase from Trypanosoma cruzi: Specificity Studies with Potential Chemotherpeutic Agents." Biochem. Pharmacol. 31, 225-229 (1982).
29. Spector, T. and Jones, T.E. "GMP Reductase from Leishmania donovani: A Possible Chemotherapeutic Target." Biochem. Pharmacol. 31, 3891-3897 (1982).
30. Nelson, D.J., LaFon, S.W., Jones, T.E., Spector,, T., Berens, R.L., and Marr, J.J. "The Metabolism of Formycin B in Leishmania donovani." Biochem. Biophys. Res. Commun. 108, 349-354 (1982).
31. Spector, T., Jones, T.E. and Beacham, L., M. III "Conversion of 2,6-Diamino-9-(2-hydroxyethoxymethyl) purine to Acyclovir as Catalyzed by Adenosine Deaminase." Biochem. Pharmacol. 32, 2505-2509 (1983).
32. Averett, D.R., Lubbers, C., Elion, G.B., and Spector, T. "Ribonucleotide Reductase Induced by Herpes Simplex Type 1: Characterization of a Distinct Enzyme." J. Biol. Chem. 258, 9831-9838 (1983).
33. Spector, T. and Averett, D.R. "A Simple Method to Purify Ribonucleotide Reductase." Analytical Biochem. 134, 467-470 (1983).
34. Spector, T., Jones, T.E., Nelson, D.J., Lafon, S.W., Berens, R.L., and Marr, J.J. "Monophosphates of Formycin B and Allopurinol Riboside: Interactions with leishmanial and Mammalian Adenylosuccinate Synthetase and GMP Reductase." Biochem. Pharmacol. 33, 1611-1617 (1984).
35. Furman, P., St. Clair, M.H., and Spector, T. "Acyclovir Triphosphate is a Suicide Inactivator of Herpes Simplex Virus DNA Polymerase." J. Biol. Chem. 259, 9575-9579 (1984).
36. Spector, T. "Progress Curve Analysis of Adenosine Deaminase Catalyzed Reactions." Analyt. Biochem. 138, 242-245 (1984).
37. Averett, D.R. and Spector, T. "Ribonucleotide Reductase of Herpes Simplex Virus Type 2 Resembles That of Herpes Simplex Virus Type I ." J. Virol. 52, 981-983 (1984).
38. Spector, T., and Ferone, R. "Folic Acid does not Inactivate Xanthine Oxidase." J. Biol. Chem. 259, 10784-10786 (1984).
39. Spector, T., and Jones, T.E. "Herpes Simplex Type I Ribonucleotide Reductase: Mechanism Studies with Inhibitors." J. Biol. Chem. 260, 8694-8697 (1985).
40. Spector, T., Averett, D.R., Nelson, D.J., Lambe, C.U., St. Clair, M.H., and Furman, P.A. "Potentiation of Acyclovir's Antiherpetic Activity by Ribonucleotide Reductase Inhibitions." Proc. Natl. Acad. Sci. 82, 4254-4257 (1985).
41. Spector, T. "Improvement of A Simple Method to Purify Ribonucleotide Reductase." Prep. Biochem. 51, 183-188 (1985).
42. Ator, M.A., Stubbe, J., and Spector, T. "Mechanism of Ribonucleotide Reductase from Herpes Simplex Virus Type 1: Evidence for 3'-Carbon-Hydrogen Bond Cleavage and Inactivation by Nucleotide Analogs." J. Biol. Chem. 261, 3595-3599 (1986).
43. Krenitsky, T.A., Spector, T., and Hall, W.W. "Xanthine Oxidase from Human Liver: Purification and Substrate Specificity." Arch. Biochem. Biophys. 247, 108-119 (1986).
44. Spector, T., Hall, W.W., and Krenitsky, T.K. "Human and Bovine Xanthine Oxidase: Mechanism Studies with Oxipurinol." Biochem. Pharmacol. 35, 3109-3114 (1986).
45. Furman, P.A., Spector, T., and Fyfe, J.A. "Acyclovir: Mechanism of Action". in "Human Herpesvirus Infections." pp. 129-140. (eds. C. Lopez & B. Roizman) Raven Press, New York (1986).
46. Spector, T. "Inhibition of the Ribonucleotide Reductases Encoded by Herpes Simplex Viruses." Pharmac. Ther. 31, 295-302 (1985) "Copyright 1987"
47. Harrington, J.A., Miller, W.H., and Spector, T. "Effector Studies of 3'-Azidothymidine Nucleotides with Human Ribonucleotide Reductase". Biochem. Pharmacol. 36, 3757-3761 (1987).
48. Spector, T. Stonehuerner, J.G., Biron, K.K., and Averett, D.R. "Ribonucleotide Reductase Induced by Varicella Zoster Virus: Characterization, and Potentiation of Acyclovir by Its Inhibition." Biochem. Pharmacol. 36, 4341-4346 (1987).
49. St. Clair, M.H., Richards, C.A., Spector, T., Weinhold, K.J., Miller, W.H., Langlois, A.L., and Furman, P.A. "3'-Azidothymidine Triphosphate as an Inhibitor and Substrate of Purified Human Immunodeficiency Virus Reverse Transcriptase." Antimicrob. Agents and Chemother. 31, 1972-1977 (1987).
50. Spector, T. "Oxipurinol as an Inhibitor of the Xanthine Oxidase Catalyzed Production of Superoxide Radical." Biochem. Pharmacol. 37, 349-352 (1988).
51. Spector, T. "Ribonucleotide Reductases Encoded By Herpes Viruses: Inhibitors and Clinical Considerations." in "International Encyclopedia of Pharmacol. and Therapeutics" Section 128, Chapter 12, pp. 235-243 (eds. J.G. Cory and A.H. Cory) Pergamon Press, New York (1989).
52. Spector, T., Harrington, J.A., Morrison, R.W., Jr., Lambe, C.U., Nelson, D.J., Averett, D.R., Biron, K., and Furman, P.A. "2-Acetylpyridine-5-[dimethylamino)thiocarbonyl]thiocarbonohydrazone (A1110U), A Potent Inactivator of Ribonucleotide Reductases of Herpes Simplex and Varicella- Zoster Viruses and a Potentiator of Acyclovir." Proc. Natl. Acad. Sci. 86, 1051-1055 (1989).
53. Resetar, A. and Spector, T. "Glucuronidation of 3'-Azido- 3'-deoxythymidine: Human and Rat Enyzme Specificity." Biochem. Pharmacol. 38, 1389-1393 (1989).
54. Reardon, J.E., and Spector, T. "Herpes Simplex Virus Type I DNA Polymerase: Mechanism of Inhibition by Acyclovir Triphosphate." J. Biol Chem. 264, 7405-7411 (1989).
55. Ellis, N.M., Lobe, D.C., and Spector, T. "Synergistic Therapy by Acyclovir and A1110U for Mice Orofacially Infected With Herpes Simplex Virus." Antimicrob. Agents Chemother. 33, 1691-1696 (1989).
56. Spector, T., Hall, W.E., Porter, D.J.T., Lambe, C.U., Nelson D.J., and Krenitsky, T.A. "Inhibition of Xanthine Oxidase by 4-hydroxy- 6-mercaptopyrazolo[3,4-d]pyrimidine." Biochem. Pharmacol. 38, 4315-4320 (1989).
57. Baum, K.F., Berens, R.L., Marr, J.J., Harrington, J.A. and Spector, T. "Purine Deoxynucleoside Salvage in Giardia Lamblia." J. Biol. Chem. 264, 21087-21090 (1989).
58. Spector, T. and Harrington, J.A. "Rapid Sampling of Multiple Enzyme Reactions." J. Virolog. Methods 26, 237-244(1989).
59. Porter, D.J.T., Harrington, J.A., Spector, T. "Herpes Simplex Type I Ribonucleotide Reductase: Selective Inactivation by A1110U and Its Iron Complex." Biochem. Pharmacol. 39, 639-46 (1990).
60. Spector, T., and Fyfe, J.A. "Synergy and Antagonism in Polymerase- targeted Antiviral Therapy: Effects of Deoxynucleoside Triphosphate Pool Modulation on Prodrug Activation." in Synergy and Antagonism in Chemotherapy (eds. T.-C. Chou and D. Rideout), pp. 285-310. Academic Press, San Diego (1991).
61. Lobe, D.C., Spector, T., and Ellis, N.M., "Synergistic Topical Therapy by Acyclovir and A1110U for Herpes Simplex Virus Induced Zosteriform Rash In Mice." Antiviral Research 15, 87-100 (1991).
62. Spector, T., Harrington, J.A., and Porter, D.J. "Human and Herpes Ribonucleotide Reductases: Inhibition by 2-acetylpyridine 5-[(2-chloroanalino)thiocarbonyl]-thiocarbonohydrozone (348U87)" Biochem. Pharmacol. 42, 91-96 (1991).
63. Resetar, A. Minick, D., and Spector, T. "Glucuronidation of 3'-Azido- 3'-deoxythymidine Catalyzed by Human Liver UDP-Glucuronosyltransferase: Significance of Nucleoside Hydrophobicity and Inhibition by Xenobiotics." Biochem. Pharmacol. 42, 559-568 (1991).
64. Koszalka, G.W, Averett, D.R., Fyfe, J.A., Roberts, G.B., Spector, T., Biron, K., and Krenitsky, T.A., "6-N-substituted Derivatives of Adenine Arabinoside as Selective Inhibitors of Varicella-Zoster Virus." Antimicrob. Agents Chemother. 35,1437-1443 (1991).
65. Harrington, J.A., and Spector, T. "Human Ribonucleotide Reductase: Activation and Inhibition by Analogs Of ATP". Biochem. Pharmacol. 42, 759-763 (1991).
66. Reardon, J.E., and Spector, T. "Acyclovir: Mechanism of Antiviral Action and Potentiation by Ribonucleotide Reductase Inhibitors." in Advances in Pharmacology vol. 22 (ed. T. August ) Academic Press, NY pp. 1-27 (1991).
67. Porter, D.J.T., Chesnut, W.G., Taylor, L.C.E., Merrill, B.M., and Spector, T, "Inactivation of Dihydropyrimidine Dehydrogenase by 5-Iodouracil" J. Biol. Chem. 266 19988-19994 (1991).
68. Lambe, C.U., Resetar, A.M., Spector, T., Koszalka, G.W, and Nelson, D.N. 'Metabolism and Pharmacokinetics of the Anti-V aricella Zoster Virus Agent 6-Dimethylaminopurine Arabinoside." Antimicrob. Agents Chemother. 36 353-360 (1992).
69. Porter, D.J.T., Chestnut, W.G., Taylor, L.C.E., Merrill, B.M., and Spector, T, "Mechanism-Based Inactivation of Dihydropyrimidine Dehydrogenase by 5-Ethynyluracil" J. Biol. Chem. 267 5236-5242 (1992).
70. Spector, T, Lobe, D.C., Ellis, M.N., Blumenkopf,T., and Szczech, G. M. "Inactivators of Herpes Simplex Virus Ribonucleotide Reductase: Hematological Profiles andIn Vivo Potentiation of the Antiviral Activity of Acyclovir" Antimicrob. Agents Chemother. 36, 934-937 (1992).
71. Averett, D.R., Steinberg, H., Koszalka, G.W, Spector, and Krenitsky, T.A., "Purine Arabinosides as Inhibitors of Hematopoietic Progenitor Cells." Antiviral Chem. Chemother. 3, 179-182 (1992).
72. Blumenkopf, T.A., Harrington, J.A., Koble, C.S., Bankstron, D.S., Morrison, R.W. Jr., Bigham, E. C., Styles, V.L., and Spector, T, "2-Acetylpyridine Thiocarbonohydrazones: Potent Inactivators of Herpes Simplex Virus Ribonucleotide Reductase" J. Med. Chem. 35, 2306-2314 (1992).
73. Furfine, ES, D'Souza, E, Ingold, K, Leban, JJ, Spector, T, and Porter, DJT, "Two-step binding mechanism for HIV Protease inhibitors" Biochemistry 31, 7886-7891 (1992).
74. Porter, DJT, and Spector, T, "Alternative substrates for calf intestinal adenosine deaminase: Pre-steady-state kinetic analysis." J. Biol. Chem. 268, 2480-2485 (1993).
75. Burns, C.L., St. Clair, M.H., Frick, L.W., Spector, T., Averett, D.R., English, M.L., Holmes, T.J., Krenitsky, T.A., and Koszalka, G.W. "Novel 6-alkoxypurine-2', 3'-dideoxynucleosides os inhibitors of the cytopathic effect of human immunodeficiency virus (HIV)" J. Med. Chem. 36, 378-384 (1993).
76. Hamzeh, F. M., Spector, T., and Leitman, P.S."2-Acetylpyridine-5-[dimethylamino)thiocarbonyl]thiocarbonohydrazone (1110U81) Potently inhibits human cytomegalovirus and potentiates the antiviral effects of ganciclovir" Antimicrob. Agents Chemother. 37, 602-604 (1993).
77. Harringinton, J.A., Reardon, J.E., and Spector, T. "AZT monophosphate: an inhibitor of exonucleolytic repair of AZT-terminated DNA" Antimicrob. Agents Chemother. 37, 918-920 (1993).
78. Spector, T, "348U87: An Inactivator of Herpes Virus Ribonucleotide Reductase That Potentiates the Antiviral Activity of Acyclovir" Drugs of The Future 18, 25-28 (1993).
79. Porter, DJT, and Spector, T, "Dihydropyrimidine dehydrogenase: kinetic Mechanism for reduction of uracil by NADPH." J. Biol. Chem. 268, 19321-19327 (1993).
80. Baccanari, D.P., Davis, S.T., Knick, V.C., and Spector, T., 5-Ethynyluracil (776C85): A potent modulator of the pharmacokinetics and antitumor activity of 5-fluorouracil" Proc. Natl. Acad. Sci. 90, 11064-11068 (1993).
81. Spector, T., Harrington, J.A., and Porter, D.J. "5-Ethynyluracil (776C85): inactivation of dihydropyrimidine dehydrogenase in vivo " Biochem. Pharmacol. 46, 2243-2248 (1993).
82. Spector, T., "5-Ethynyluracil (776C85): An Inactivator of Uracil Reductase That Potentiates the Antitumor Activity of 5-Fluorouracil" Current Opinions in Therapeutic Patents. 3, 1751-1754 (1993)
83. Cao, S., Rustum, Y. M., and Spector, T. "5-Ethynyluracil (776C85): Modulation of 5-Fluorouracil Efficacy and Therapeutic Index in Rats Bearing Advanced Colorectal Carcinoma" Cancer Res. 54, 1507-1510 (1994).
84. Spector, T, "Writing a Scientific Manuscript: Highlights For Success" J. Chem. Education 71, 47-50 (1994).
85. Porter, D.J., Harrington, J.A., Almond, M.R., Lowen, G.T., Zimmerman, T.P., and Spector, T., "5-Ethynyl-2(1H)-pyrimidinone: aldehyde oxidase-activation to 5-ethynyluracil (776C85), a mechanism-based inactivator of dihydropyrimidine dehydrogenase" Biochem. Pharmacol. 47, 1165-1171 (1994).
86. Porter, D. J. T., Harrington, J. A., Almond, M. R., Lowen, G. T. and Spector, T., "(R)-5-Fluoro-5,6-dihydrouracil: kinetics of oxidation by dihydropyrimidine dehydrogenase and hydrolysis by dihydropyrimidine aminohydrolase" Biochem. Pharmacol. 48, 775-779 (1994).
87. Spector, T., Porter, D. J. T., Nelson, D. J., Baccanari, D. P., Davis, S. T., Almond, M. R., Khor, S. P., Amyx, H., Cao, S., and Rustum, Y. M., "5-Ethynyluracil (776C85), A Modulator Of The Therapeutic Activity Of 5-Fluorouracil" Drugs of The Future 19, 565-571 (1994).
88. Davis, S. T., Joyner, S.S., Baccanari, D. P., and Spector, T., "5-Ethynyluracil (776C85): protection from 5-fluorouracil-induced neurotoxicity in dogs" Biochem. Pharmacol. 48, 233-236 (1994).
89. Spector, T., Cao, S., Rustum, Y.M., Harrington, J A., and Porter, D. J. T. "Attenuation of The Antitumor Activity of 5-Fluorouracil By (R)-5-Fluoro-5,6-dihydrouracil" Cancer Res. 55, 1239-1241 (1995).
90. Fischel, J. L., Etinne, M. C., Spector, T., Formento, P., Renee, N., and Milano, G., "Dihydropyrimidine dehydrogenase: A tumoral target for fluorouracil modulation" Clin. Cancer Res. 1, 991-996 (1995).
91. Porter, D.J.T., Harrington, J. A., Almond, M, Chestnut, W.G., Tanoury, G., and Spector, T, "Enzymatic Elimination of Fluoride From a-Fluoro-b-alanine" Biochem. Pharmacol. 50, 1475-1484 (1995).
92. Cao, S., Baccanari, D. P., Joyner, S. S., Davis, S. T., Rustum, Y. M., and Spector, T., "5-Ethynyluracil (776C85): Effects on the Antitumor Activity and Pharmacokinetics of Tegafur, a Prodrug of 5-Fluorouracil" Cancer Res. 55, 6227-6230 (1995).
93. Khor, S-P, Amyx, H., Davis, S., Nelson, D. J., Baccanari, D. P., and Spector, T., "Dihydropyrimidine Dehydrogenase Inactivation and 5-Fluorouracil Pharmacokinetics: Allometric Scaling of Animal Data, Pharmacokinetics and Toxicodynamics of 5-Fluorouracil in Humans" Cancer Chemother. Pharmacokinetics. 39, 233-238 (1997).
94. Baker, S. D., Khor, S. P., Adjei, A. A., Doucette, M., Spector, T., Amin, J. M., Jersey, J., Donehower, R.C., Grochow, L. B., Sartorius, S. E., Noe, D. A., Hohneker, J. A., and Rowinsky, E. K., "Pharmacokinetic, Oral Bioavailability, and Safety Study of 5-Fluorouracil in Patients Treated with 776C85, and Inactivator of Dihydropyrimidine Dehydrogenase". J. Clin. Oncology 14, 3085-3096 (1996).
95. Fischel, J. L., Formento, P., Etinne, M. C., Spector, T., Renee, N., and Milano, G., "Dual modulation of 5-fluorouracil cytotoxicity using folinic acid with a dihydropyrimidine dehydrogenase inhibitor." Biochem. Pharmacol. 53, 1703-1709 (1997).
96. Arellano, M., Malet-Martino, M., Martino, R. and Spector, T., "5-Ethynyluracil (GW776): Effects on the Formation of the Toxic Catabolites of 5-Fluorouracil, Fluoroacetate and Fluorohydroxypropionic Acid, in the Isolated Perfused Rat Liver Model." British J. Cancer 76, 1170-1180 (1997).
97. Adams, E.R., Leffert, J.J., Craig, D.J., Spector, T., Pizzorno,G., "In Vivo Effect of 5-Ethynyluracil on 5-Fluorouracil Metabolism Determined by 19F-NMR Spectroscopy". Cancer Res. 59, 122-7 (1999).
98. Baker SD, Diasio RB, O'Reilly S, Lucas VS, Khor SP, Sartorius SE, Donehower RC, Grochow LB, Spector T, Hohneker JA, Rowinsky EK, "Phase I and Pharmacologic Study of Oral Fluorouracil on a Chronic Daily Schedule in Combination With the Dihydropyrimidine Dehydrogenase Inactivator Eniluracil". J Clin Oncol 18, 915- 926 (2000).
99. Bading JR, Alauddin MM, Fissekis JD, Shahinian AH, Joung J, Spector T, Conti PS. "Blocking catabolism with eniluracil enhances PET studies of 5-[18F]fluorouracil pharmacokinetics." J Nucl Med 41, 1714-1724 (2000).
100. Cao, S., Baccanari, D. P., Rustum, Y. M., Davis,S.T., Tansik, R., Porter, D..J. T., and Spector, T., "(R)a-Fluoro-b-Alanine: Effects on the Antitumor Activity and Toxicity of 5-Fluorouracil". Biochem. Pharmacol. 59, 953-960 (2000).
101. Paff MT Baccanari DP Davis ST Cao SS Tansik RL Rustum YM Spector T., " Preclinical development of eniluracil: Enhancing the therapeutic index and dosing convenience of 5-fluorouracil." Invest. New Drugs. 18, 365-371 (2000).
102. Galbusera C, Orth P, Fedida D, and Spector T. Superoxide Radical Production
By Allopurinol and Xanthine Oxidase. Biochem. Pharmacol. 71:1747-52. (2006).
_________________________________________________________________
XII. Patents
1. Spector, T., Averett, D.R., and Nelson, D.J. "Antiviral Combinations." July 19, 1988 United States Patent #4,758,572.
2. Spector, T., Averett, D.R., and Nelson, D.J. "Antiviral Combinations (Hu)." 1986 United States patent filing.
3. Namm, D.H. and Spector, T. "Protection of Ischemic Tissues from Reperfusion Injury by Oxypurinol ." March 1987 Worldwide Filings.
4. Namm, D.H. and Spector, T. "Protection of Ischemic Tissues from Reperfusion Injury by Oxypurinol and t-pa." March 1987 Worldwide Filings.
5. Spector, T., and Averett, D.R. "Antiviral Combinations For Treatment of Varicella Zoster Infections." 1989 Worldwide Filings.
6. Spector, T., Porter, D.J.T., and Rahim, G. "Protection from AZT-Induced Toxicity by Inactivators of Uracil Reductase (related)". July 1991 Patents issued 5643913 (July1997)
7. Spector, T., Porter, D.J.T., and Rahim, G. "Protection from AZT-Induced Toxicity by Inactivators of Uracil Reductase". July 1991 Patents issued US 6,177,436 B1. (April 2001)
8. Spector, T., Porter, D.J.T., and Rahim, G. "Protection from AZT-Induced Toxicity by Inactivators of Uracil Reductase (related)". July 1991 Patents issued US 6,221,852 B1. (June 2001)
9. Spector, T., Porter, D.J.T., and Rahim, G. "Potentiation of the Antitumor Activity of 5-Fluorouracil by Inactivators of Uracil Reductase (related)". Sept 1991 Patent issued WO 92/04901 (April 1992)
10. Spector, T., Porter, D.J.T., and Rahim, G. "Potentiation of the Antitumor
Activity of 5-Fluorouracil by Inactivators of Uracil Reductase (related)".
Sept 1991 The following Patents were issued:
Patent Number (Date Issued)
5643913 (1997)
5817664 (1998)
6177436 (2001)
6221852 (2001)
6268374 (2001)
6297223 (2001)
6586440 (2003)
7119096 (2006)
11. Blumenkopf, T.A., Spector, T., Averett, D.R., Morrison, R.W.Jr., Bigham, E.C., and Styles, V.L. "Antiviral Combinations and Compounds Therefor." United States Patent issued 5,175165.(December 1992)
12. Blumenkopf, T.A., Spector, T., Averett, D.R., Morrison, R.W.Jr., Bigham, E.C., and Styles, V.L. "Antiviral Combinations and Compounds Therefor." United States Patent issued 5,393,883.(Feb. 1995)
13. Spector et al. (inventors to be determined) "Substituted uracil derivatives as lipid lowering agents". UK Filing Oct. 28, 1994.
14. Spector et al. “Methods For Administering DPD Inhibitors In Combination
With 5-FU And 5-FU Prodrugs”. Filed: Dec. 5, 2005,