Susan B. Gates
Eli Lilly and Company
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Featured researches published by Susan B. Gates.
Advances in Enzyme Regulation | 1996
Laurane G. Mendelsohn; Susan B. Gates; Lillian L. Habeck; Katherine A. Shackelford; John F. Worzalla; Chuan Shih; Gerald B. Grindey
We have studied the molecular effects of a LFD in a murine model in order to better define the biochemical changes associated with folate deficiency. In addition, we have demonstrated the effect of a LFD on the pharmacokinetic profile and therapeutic activity and toxicity of lometrexol. These studies showed increased density of FR in tumors implanted in LFD mice and a decrease in the affinity of these receptors for folic acid. The results suggest that tumors can compensate for low folate bioavailability by up-regulation of a second FR with slightly lower affinity for folic acid. The higher density of this FR would provide greater capacity for garnering serum folate. FPGS activity increased in several tumors and liver and kidney of LFD mice. The increase in this enzyme activity would result in enhanced polyglutamation of folates and classical antifolates and thus increased cellular retention. Consistent with these changes in liver FPGS, mice injected i.v. with a single dose of lometrexol accumulated significantly more drug in liver and tumors of LFD animals compared to SD mice. Also, higher liver concentrations of lometrexol persisted longer in LFD mice. Polyglutamate analysis showed that longer polyglutamate forms appeared earlier in liver of LFD mice. After 7 days, longer polyglutamyl forms were recovered from liver of LFD mice (octa- and hepta-glutamyl lometrexol) compared to those on SD. A comparison of the efficacy and toxicity of lometrexol in C3H mammary tumor-bearing mice showed that in mice on LFD, lometrexol treatment produced a delayed toxicity with an LD50 of 0.1-0.3 mg/kg, a 3000-fold increase in lethality compared to SD mice. Supplementation of mice with folic acid restored anti-tumor activity and increased the therapeutic dose-range over which efficacy could be assessed. These studies support the use of folic acid supplementation for cancer patients treated with antifolate therapy in order to prevent the biochemical changes in FR and FPGS associated with folate deficiency, prevent delayed toxicity to GARFT inhibitors and enhance the therapeutic potential of this class of drugs.
Biochemical Pharmacology | 1996
Susan B. Gates; John F. Worzalla; Chuan Shih; Gerald B. Grindey; Laurane G. Mendelsohn
The importance of polyglutamation for the activation of natural folates and classical antifolates and recent evidence for the role of dietary folate as a biochemical modulator of antifolate efficacy led us to investigate the influence of changes in dietary folate on folylpolyglutamate synthetase (FPGS) activity. Activities were measured using lometrexol (6R-5,10-dideazatetrahydrofolic acid) as a substrate for FPGS with extracts of murine tissues, murine tumors, and human tumor xenografts from mice on standard diet or low folate diet. Tissues and tumors from mice on standard diet exhibited a 6-fold range of FPGS activity. Kidney had the lowest activity (36 pmol/hr.mg protein), followed by the human xenograft PANC-1 pancreatic carcinoma (46 pmol/hr.mg protein), liver (109 pmol/hr.mg protein), murine C3H mammary tumor (112 pmol/hr.mg protein), and the human xenograft MX-1 mammary carcinoma (224 pmol/hr.mg protein). In response to restricted dietary folate, four out of five tissues had significantly increased (25-50%) FPGS activity. Only the tumor with highest FPGS activity under standard diet conditions (MX-1 mammary) did not respond to low folate diet. The results indicate that changes in dietary folate intake can modulate FPGS activity significantly in vivo and suggest that the tissue distribution and toxicities of classical antifolates requiring polyglutamation for activation and cellular retention will be influenced significantly by folate status of the host.
Bioorganic & Medicinal Chemistry Letters | 1996
Lynn S. Gossett; Lillian L. Habeck; Susan B. Gates; Sherri L. Andis; John F. Worzalla; Richard M. Schultz; Laurane G. Mendelsonn; William Kohler; Manohar Ratnam; Gerald B. Grindey; Chuan Shih
Abstract A novel series of dihydrofolate reductase inhibitors was uncovered during an expansion of the SAR of 5,10-dideazatetrahydrofolic acid, and their biological activity was evaluated. These new analogs do not possess an oxygen at the 4 position and contain a monocyclic pyrimidine ring.
Bioorganic & Medicinal Chemistry Letters | 1999
Lynn S. Gossett; Lillian L. Habeck; Katherine A. Shackelford; Laurane G. Mendelsohn; Susan B. Gates; John F. Worzalla; Tracy D. Self; Karla S. Theobald; Sherri L. Andis; Richard M. Schultz; Chuan Shih
A new series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates 1-3 were synthesized through an efficient conversion of 2-pivaloyl-4-oxo-6-ethynylpyrido[2,3-d]pyrimidine 5 to the corresponding 4-amino analog 7 via the activated 1,2,4-triazole intermediate 6. Compound 7 was used as the key intermediate for the preparation of the final products. The detailed biological evaluation of these compounds both as antineoplastic and antiarthritic agents will be discussed.
Cancer Research | 1997
Chuan Shih; Victor J. Chen; Lynn S. Gossett; Susan B. Gates; Warren Cameron Mackellar; Lillian L. Habeck; Katherine A. Shackelford; Lurane G. Mendelsohn; Daniel J. Soose; Vinod F. Patel; Sherri L. Andis; Jesse R. Bewley; Elizabeth A. Rayl; Barbara A. Moroson; G. Peter Beardsley; William Kohler; Manshan Ratnam; Richard M. Schultz
Journal of Medicinal Chemistry | 1997
John E. Toth; Gerald B. Grindey; William J. Ehlhardt; James E. Ray; George B. Boder; Jesse R. Bewley; Kim K. Klingerman; Susan B. Gates; Sharon M. Rinzel; Richard M. Schultz; Leonard C. Weir; John F. Worzalla
Clinical Cancer Research | 1996
Susan B. Gates; Laurane G. Mendelsohn; Katherine A. Shackelford; Lillian L. Habeck; Jonathan D. Kursar; Lynn S. Gossett; John F. Worzalla; Chuan Shih; Gerald B. Grindey
Journal of Pharmacology and Experimental Therapeutics | 1998
John L. Tonkinson; Lillian L. Habeck; John E. Toth; Laurane G. Mendelsohn; Jesse R. Bewley; Katherine A. Shackelford; Susan B. Gates; James D. Ray; Victor J. Chen
Oncology Research | 1995
Richard M. Schultz; Sherri L. Andis; Katherine A. Shackelford; Susan B. Gates; Manohar Ratnam; Laurane G. Mendelsohn; Chuan Shih; Gerald B. Grindey
Journal of Molecular Biology | 2001
Peter Sayre; Janet Finer-Moore; Timothy A Fritz; Donna Biermann; Susan B. Gates; Warren Cameron Mackellar; Vinod F. Patel; Robert M. Stroud