The Zeeh Pharmaceutical Experiment Station, located within the School of Pharmacy, is designed to supportthe early-stage pharmaceutical development needs of University-based and regional industry drug discoverylaboratories. The Station brings substantial industrial drug development experience to the UW NCDDGworking team, enabling it to build strategic advantage into their evolving tactical plans in meeting their longterm program goals.In the early stages of the NCDDG molecule synthesis effort, a small number of class-representativenatural product compounds will be carefully selected and used as the basis for the development of semiquantitativeanalytical methodology useful for preparation and in vitro assessment of the compounds. Forcompounds passing the initial in vitro biological activity criteria, selected representative candidates will betested for their physicochemical properties which relate to their performance in vivo, e.g. solubility and cellpermeability, to offer some guidance to the downstream testing work. In further support of in vivo studies,the Station will prepare and test (including relevant stability in vitro) formulations of approximately 16 drugcandidates selected on the basis of in vitro studies (as above) for studies of PK/metabolism in mice (permodel) at a set dose of approximately 0.5 mg/kg. In accordance with the half-lives so determined, acutetoxicology evaluation (MTD) will follow in mice (per model). From these PK/metabolism and acutetoxicology results, it is expected that 12 compounds will be chosen based on their half-life and MTD for studyin the four animal efficacy models.Station will also provide the UW NCDDG team Lab Program 3 with a coordinated administrativeinterface to the School of Pharmacy AAALAC-accredited animal facility in which mice will be housed oncethe animal models have been fully developed and will support all or a large proportion of the breedingcolonies and test animal populations for pharmacokinetics (PK) - compound half-life, dose titration;determination of MTD; acute toxicology (MTD, non-GLP); and mouse efficacy screening. The Station willalso coordinate with the Bioanalytical (GLP) laboratory in the UWCCC for the analysis of blood samplesdrawn on behalf of the PK-related studies, and will manage the data analysis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19CA113297-01
Application #
6934168
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$26,308
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kim, Soyoung; Alexander, Caroline M (2014) Tumorsphere assay provides more accurate prediction of in vivo responses to chemotherapeutics. Biotechnol Lett 36:481-8
Lohman, Jeremy R; Huang, Sheng-Xiong; Horsman, Geoffrey P et al. (2013) Cloning and sequencing of the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics. Mol Biosyst 9:478-91
Yang, Dong; Li, Wenli; Huang, Sheng-Xiong et al. (2012) Functional characterization of ttnI completing the tailoring steps for tautomycetin biosynthesis in Streptomyces griseochromogenes. Org Lett 14:1302-5
Kim, Soyoung; Roopra, Avtar; Alexander, Caroline M (2012) A phenotypic mouse model of basaloid breast tumors. PLoS One 7:e30979
Lin, Shuangjun; Huang, Tingting; Horsman, Geoff P et al. (2012) Specificity of the ester bond forming condensation enzyme SgcC5 in C-1027 biosynthesis. Org Lett 14:2300-3
Huang, Sheng-Xiong; Yu, Zhiguo; Robert, Francis et al. (2011) Cycloheximide and congeners as inhibitors of eukaryotic protein synthesis from endophytic actinomycetes Streptomyces sps. YIM56132 and YIM56141. J Antibiot (Tokyo) 64:163-6
Liu, Sijiu; Yu, Zhihong; Yu, Xiao et al. (2011) SHP2 is a target of the immunosuppressant tautomycetin. Chem Biol 18:101-10
Chen, Yihua; Yin, Min; Horsman, Geoff P et al. (2011) Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus. J Nat Prod 74:420-4
Yang, Dong; Zhu, Xiangcheng; Wu, Xueyun et al. (2011) Titer improvement of iso-migrastatin in selected heterologous Streptomyces hosts and related analysis of mRNA expression by quantitative RT-PCR. Appl Microbiol Biotechnol 89:1709-19
Yu, Zhiguo; Zhao, Li-Xing; Jiang, Cheng-Lin et al. (2011) Bafilomycins produced by an endophytic actinomycete Streptomyces sp. YIM56209. J Antibiot (Tokyo) 64:159-62

Showing the most recent 10 out of 97 publications