This project is aimed at developing plant tissue biotechnology for the production of taxol and taxol efflux blockers to improve the availability of taxol for further clinical evaluations and overcome taxol-resistance problems. This objective will be accomplished by a consortium which is multidisciplinary (analytical chemistry, biochemistry, natural product chemistry, molecular biology, and pharmacology) and multi-institutional (Purdue University and Upjohn Company). We propose to: (1) develop suspension tissue cultures and hairy root cultures of Taxus species; (2) analyze and select high yielding colonies by tubulin stabilization and tandem mass spectrometry/high performance liquid chromatography; (3) develop highly sensitive and compound-selective tandem mass spectrometric methods for taxol and other taxanes; (4) enhance production of taxol and desirable taxanes by induction with elicitors and transformation with various Agrobacterium strains; (5) prescreen potential taxol efflux blockers from tissue cultures; (6) perform biological and physical assay- directed isolation, and elucidate the structures of desirable constituents; (7) synthesize taxol from baccatin III or other related taxanes; and (8) evaluate antitumor activity of novel taxanes in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055118-02
Application #
3199559
Study Section
Special Emphasis Panel (SRC (52))
Project Start
1991-09-20
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Purdue University
Department
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Chen, X Y; Wang, M; Chen, Y et al. (1996) Cloning and heterologous expression of a second (+)-delta-cadinene synthase from Gossypium arboreum. J Nat Prod 59:944-51
Hoke 2nd, S H; Cooks, R G; Chang, C J et al. (1994) Determination of taxanes in Taxus brevifolia extracts by tandem mass spectrometry and high-performance liquid chromatography. J Nat Prod 57:277-86
Hoke 2nd, S H; Wood, J M; Cooks, R G et al. (1992) Rapid screening for taxanes by tandem mass spectrometry. Anal Chem 64:2313-5