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To: scaram(o)uche who wrote (9)10/15/2000 6:27:00 PM
From: scaram(o)uche  Respond to of 887
 
Just parking, and for comment, from S-1....

Executive Officers, Directors and Key Personnel

The following table sets forth information regarding our executive officers,
directors and key personnel.

<TABLE>
<CAPTION>
Name Age Position
- ---- --- --------
<S> <C> <C>
Executive Officers and
Directors
Michael M. Wick, MD, PhD.. 54 President, Chief Executive Officer and Chairman
Cynthia M. Butitta........ 45 Chief Financial Officer
Reinaldo F. Gomez, PhD.... 54 Vice-President, Corporate Alliances
David R. Bethune.......... 59 Director
Jean Deleage, PhD......... 59 Director
Jerrold L. Glick.......... 57 Director
David W. Martin, Jr., MD.. 59 Director
Stefan Ryser, PhD......... 40 Director

Key Personnel
Michael R. Kozlowski,
PhD...................... 46 Vice President, Biology Research
Steven R. Schow, PhD...... 50 Vice President, Chemistry Research
Hugo O. Villar, PhD....... 41 Vice President, Discovery Technologies
</TABLE>

Michael M. Wick, MD, PhD has served as our Chairman of the board of directors
since January 2000, as our Chief Executive Officer since July 1999 and as our
President since June 1998. Dr. Wick served as our Chief Operating Officer from
December 1997 until June 1998, and as our Executive Vice President, Research
and Development, from December 1997 until June 1998. He has been one of our
directors since December 1997. Prior to joining us in December 1997, Dr. Wick
was Senior Vice President of Research for CV Therapeutics, a public
biotechnology company, from May 1995 until May 1997 and continued as a
consultant until December 1997. Dr. Wick served as Executive Director of
oncology/immunology and clinical research at Lederle Laboratories, a division
of American Cyanamid, a pharmaceutical company, from September 1990 until May
1995, and also directed the Cynamid/Immunex joint oncology research program.
Dr. Wick began his career at Harvard Medical School, where he served as an
Associate Professor from July 1981 until June 1994 and Chief of the Melanoma
Clinic and Laboratory of Molecular Dermatological Oncology at the Dana Farber
Cancer Institute from September 1980 until September 1992. Dr. Wick holds a PhD
degree in chemistry from Harvard University and an MD degree from Harvard
Medical School.

Cynthia M. Butitta has served as our Chief Financial Officer since August
1998. Ms. Butitta also provides financial consulting services as a Partner in
Altair Capital Associates LLC, which she co-founded in November 1998, and
Butitta Consulting Services LLC, which she founded in September 1997. From
December 1995 until September 1997, Ms. Butitta was Vice President of Finance
and Administration and Chief Financial Officer for Connetics, Inc., a
biotechnology company. From June 1994 until December 1995, she was Vice
President of Finance and Administration and Chief Financial Officer for InSite
Vision, Inc., a biotechnology company. Ms. Butitta holds a BS degree in
business and accounting from Edgewood College in Madison, Wisconsin, and an MBA
degree in finance from the University of Wisconsin, Madison.

Reinaldo F. Gomez, PhD has served as our Vice President, Corporate Alliances
since January 1998. He served as our Vice President, Research and Development
from September 1996 until December 1997. From August 1995 to September 1996,
Dr. Gomez served as our Vice President, Project Management. Dr. Gomez served as
our Chief Executive Officer from July 1992 to August 1995. He served as our
President from May 1991 until August 1995 and as one of our directors from

40
<PAGE>

May 1991 until January 1997. Over a ten-year period prior to that, Dr. Gomez
held various research positions at Genentech, Inc., a biotechnology company,
including that of Vice President of Discovery Research. During his tenure at
Genentech, Dr. Gomez directed that company's major drug development effort for
tissue plasminogen activator (t-PA), which led to the filing of the application
for FDA marketing approval in 1986. He previously served on the faculty of the
Massachusetts Institute of Technology (MIT) as Associate Professor in Nutrition
and Food Science. Dr. Gomez received his BS and MS degrees in food science from
the University of Florida and his PhD in nutrition and food science from MIT.

David R. Bethune has served as one of our directors since December 1999. Mr.
Bethune has 34 years of experience in the pharmaceutical and biopharmaceutical
industries. Since February 2000, he has served as Chairman and Chief Executive
Officer of Atrix Laboratories, a pharmaceutical company, and became acting
Chief Executive Officer of Atrix in August 1999. He has also served as a
director of Atrix since April 1995. From July 1997 until October 1998, Mr.
Bethune was President and Chief Operating Officer of IVAX Corporation, a
pharmaceutical company. From March 1995 until June 1997, he served as President
and Chief Executive Officer for Aesgen, Inc., a pharmaceutical company. Mr.
Bethune has held various positions at American Cyanamid Company, a
pharmaceutical company, from February 1988 until February 1995. Mr. Bethune
also served as President of Operations and Vice President and General Manager
of U.S. Pharmaceuticals for G. D. Searle & Co., a pharmaceutical company, from
June 1984 until January 1988. Mr. Bethune is a director of St. Charles
Pharmaceutical Co., a pharmaceutical company, and the Female Health Company, a
company that sells female health products. Mr. Bethune holds an AB degree in
Accounting and Finance from Lenoir-Rhyne College and a masters degree in
Executive Management from Columbia University.

Jean Deleage, PhD has served as one of our directors since August 1994. Dr.
Deleage is a founder and Managing General Partner of Alta Partners, a venture
capital partnership investing in information technologies and life science
companies. From 1979 to 1996, Dr. Deleage was a Managing Partner of Burr, Egan,
Deleage & Co., a venture capital firm. Dr. Deleage was a founder of Sofinnova,
a venture capital organization in France, and Sofinnova, Inc., a U.S.
subsidiary of Sofinnova. Dr. Deleage is a director of Flamel Technologies S.A.,
a polymer engineering company and Aclara Biosciences, Inc., a biotechnology
company. In 1993, he was awarded the Ordre National du Merite and the Legion of
Honor from the French government. Dr. Deleage received a Baccalaureate in
France, an MS degree in electrical engineering from Ecole Superieure
d'Eletricite and a PhD in economics from the Sorbonne.

Jerrold L. Glick has served as one of our directors since 1988, as our
Chairman of the board from 1988 until November 1995, and as our Secretary from
December 1988 until November 1990. Mr. Glick has been a General Partner of
Columbia Group Limited, LLP, a real estate development company, since 1972. In
1991, Mr. Glick founded QualiCenters, Inc., a multi-state provider of dialysis
services and served as its secretary and director until 1997. He is a director
of Urban Ventures LLC, a real estate development company; director, Secretary
and Vice President of AML/APL, Inc., a clinical laboratory services company;
director and Secretary of RV Management Corp., a multi-state provider of
dialysis services; and director of Republic Financial Corporation, a financial
services company. Mr. Glick received a BS degree in finance from the University
of Southern California.

David W. Martin, Jr., MD has served as one of our directors since August
1997. In July 1997, Dr. Martin co-founded Eos Biotechnology, Inc., a
biotechnology company, and has been its President and Chief Executive Officer
since July 1997. From May 1995 until November 1996, he served as President and
Chief Executive Officer of Lynx Therapeutics, a company that develops
technology for measuring gene activities. From January 1994 until April 1995,
Dr. Martin held various positions at Chiron Therapeutics, a biotechnology
company. He was Executive Vice President of Research and

41
<PAGE>

Development at The DuPont Merck Pharmaceutical Co., a pharmaceutical company,
from January 1991 until January 1994. From January 1983 until September 1990,
Dr. Martin served as the first Vice President of Research and Development of
Genentech, a biotechnology company. Dr. Martin is a director of Varian Medical
Systems, Inc., a spin-off of Varian Associates, Inc., a company that develops
and markets radiation equipment and software, and Cubist Pharmaceuticals, Inc.,
a company that discovers and develops anti-infective drugs. Dr. Martin holds an
MD degree from Duke University.

Stefan Ryser, PhD has served as one of our directors since September 1998.
Dr. Ryser has served as Chief Executive Officer, member and delegate of the
board of International Biomedicine Management Partners Inc., a company that
manages investments in biotechnology companies on behalf of International BM
Biomedicine Holdings Inc., since January 1998. From January 1989 until December
1997, Dr. Ryser held various positions at F. Hoffmann-La Roche Ltd. (Roche), a
pharmaceutical company, including Scientific Assistant to the President of
Global Research and Development, and was responsible for maintaining the
scientific liaison between Roche and Genentech. From January 1991 until
December 1997, Dr. Ryser served as a member of the Brussels-based senior
advisory group of EuropaBio, a European biotechnology organization. Dr. Ryser
is a director of Genaissance Pharmaceuticals, Inc., a genomics company; Arena
Pharmaceuticals, a biotechnology company, and Cytokinetics, Inc., a
biotechnology company. Dr. Ryser received a PhD degree in molecular biology
from the University of Basel.

Michael R. Kozlowski, PhD has served as our Vice President of Biology
Research since March 2000. He served as our Senior Director of Discovery
Biology from June 1998, and as our Director of Pharmacology since March 1998.
Prior to joining us, Dr. Kozlowski served as a Program Director and Director of
Assay Development and Screening at Geron Corporation, a biotechnology company,
from January 1994 until March 1998. Dr. Kozlowski was a Senior
Scientist/Principle Scientist at Bristol-Myers Squibb Co., a pharmaceutical
company, from June 1987 until December 1993. Dr. Kozlowski earned his BS in
biology from The California Institute of Technology in June 1976 and his PhD in
biology in March 1983 from the University of California at Irvine.

Steven R. Schow, PhD has served as our Vice President of Chemistry Research
since March 2000. He served as our Senior Director of Medicinal Chemistry from
March 1998 until March 2000. Prior to joining us, Dr. Schow served as a
Director of Medicinal Chemistry at CV Therapeutics, a biotechnology company,
from May 1995 to March 1998. He served as a Senior Group Leader at Lederle
Laboratories, a division of American Cyanamid, a pharmaceutical company, from
November 1991 until May 1995. Dr. Schow earned his PhD degree in organic
chemistry in October 1977 from the University of California at Los Angeles.

Hugo O. Villar, PhD has served as our Vice President, Discovery Technologies
since February 1998. Dr. Villar previously served as our Director of Chemistry
from May 1995 until February 1998, and as a Senior Scientist from October 1992
to May 1995. Prior to joining us, Dr. Villar served as a director of
computational pharmacology at Molecular Research Institute, a not-for-profit
research organization, from July 1989 until October 1992. He was also a
computational chemist at SRI International, a not-for-profit research
organization, from May 1988 until June 1989. Dr. Villar earned an MS degree in
December 1981 and PhD degree in December 1985 in chemistry from the Universidad
Nacional de La Plata, Argentina.



To: scaram(o)uche who wrote (9)10/15/2000 6:32:33 PM
From: scaram(o)uche  Read Replies (1) | Respond to of 887
 
Mol Pharmacol 2000 Jul;58(1):167-74

Cellular response to a glutathione S-transferase P1-1 activated prodrug.

Rosario LA, O'Brien ML, Henderson CJ, Wolf CR, Tew KD

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

TER286 [gamma-glutamyl-alpha-amino-beta(2-ethyl-N,N,N',
N'-tetrakis(2-chloroethyl)phosphorodiamidate)-sulfonyl-propionyl-( R)- (-) phenylglycine] is a
novel nitrogen mustard prodrug that is preferentially activated by glutathione S-transferase P1-1
(GSTP1-1). A human promyelocytic leukemia /TER286-resistant cell line was selected by
chronic, long-term exposure to the prodrug. Although resistance was not readily achieved,
eventually a 5-fold resistant clone was isolated. Cross-resistance to melphalan occurred, but not
to doxorubicin (Adriamycin), taxol, and gamma-glutamyl-S-(benzyl)cysteinyl-R(-)-phenyl glycine
diethyl ester, a GSTP1-1 inhibitor. The protein and transcript levels and enzymatic activity of
GSTP1-1 were reduced significantly in the selected resistant line. GSTalpha levels were
unchanged, and GSTmu was undetectable. Although glutathione levels were elevated in human
promyelocytic leukemia/TER286 cells, no changes in the expression of thiol-related genes
including gamma-glutamylcysteine synthetase, gamma-glutamyl transpeptidase, or multidrug
resistance protein were found. A 7-fold increase in catalase expression in the resistant cell line
indicated an adaptive response to oxidative and electrophilic stress, and this was also reflected in
the lower prevalence of drug-induced DNA single-strand breaks in the resistant cells. Mouse
embryo fibroblast GSTP1-1(-/-) cells exhibited 2-fold resistance to TER286 compared with
GSTP1-1(+/+) cells. NIH3T3 cells transfected with combinations of gamma-GCS and multidrug
resistance protein exhibited enhanced resistance to TER286, although the degree of resistance
was impaired by cotransfection of GSTP1-1. These results are consistent with responses in the
TER286-resistant cells indicative of GSTP1-1-mediated mechanism of activation. In
consequence, these data support the rationale that tumors expressing high levels of GSTP1-1 will
be more sensitive to the cytotoxic effects of the drug.



To: scaram(o)uche who wrote (9)10/15/2000 6:50:36 PM
From: scaram(o)uche  Respond to of 887
 
Switching gears from tumor-activated prodrug to a purported G-CSF replacement, this abstract is unrelated to its intended clinical applications????......

J Pharmacol Exp Ther 1999 Dec;291(3):1348-55

Glutathione peptidomimetic drug modulator of multidrug resistance-associated protein.

O'Brien ML, Vulevic B, Freer S, Boyd J, Shen H, Tew KD

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,
USA.

The peptidomimetic drug gamma-glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine diethyl ester
(TER199) is an analog of glutathione designed to be an isozyme-specific inhibitor of GSTP1-1
protein1-1. This compound (and the de-esterified moiety) is shown to be an effective inhibitor of
multidrug resistance-associated protein1 (MRP1)-mediated drug resistance. Kinetic analyses
revealed that gamma-glutamyl-S-(benzyl)cysteinyl-R-(-)-phenyl glycine reversibly inhibits the
transport of 2,4-dinitrophenyl-S-glutathione with a K(i) of 752 &mgr;M. TER199 reversed the
accumulation deficit of daunorubicin in MRP1-transfected NIH3T3 fibroblasts and maintained
intracellular levels for >2 h after daunorubicin removal. Cytotoxicity assays revealed that TER199
significantly reversed the resistance of MRP1-transfected NIH3T3 cells for vincristine,
doxorubicin, etoposide, and mitoxantrone. HL-60 cells made resistant to TER199 by chronic,
long-term selection had increased mRNA and protein levels of multidrug resistance-associated
protein, MRP1, and gamma-glutamyl cysteine synthetase heavy and light subunits (the
rate-limiting enzyme in GSH synthesis). In spite of increased gamma-glutamyl cysteine synthetase,
their glutathione content was reduced approximately 35% from that of parental HL-60 cells.
These cells also exhibited a drug resistance profile commensurate with the previously described
MRP1 overexpressing phenotype, with resistance to Vinca alkaloids, epipodophyllotoxins, and
anthracyclines; additional cross-resistance to paclitaxel (Taxol), mitoxantrone, and 5-fluorouracil
was observed.