This proposal describes a research program involving synthetic, mechanistic/mode of action, and biological studies of molecules with demonstrated or potential relevance to cancer research and treatment. The long-term objectives of this program are: (1) to elucidate the specific functions of microtubules in signal transduction pathways that regulate the cell cycle, and (2) to design and synthesize new molecules to probe, and ultimately control, the functions of microtubules in cells. The key question that we wish to address is: What is the cellular mechanism that induces cell cycle arrest and cell death in response to anticancer drugs such as taxol that bind to microtubules? The specific aims of this application are: (1) to determine if the cytotoxicit displayed by microtubule-binding drugs results from inhibition of microtubule dynamics, (2) to discover how cells monitor the integrity of microtubules, and (3) to synthesize and analyze new high-affinity microtubule ligands. The principal methodologies that we will employ are organic synthesis, protein biochemistry, and molecular biology. We will synthesize molecules that bind to microtubules, and these compounds will be examined as inhibitors of microtubul dynamics and as cytotoxic agents. Biochemical and genetic approaches will be used to identify proteins that display drug-dependent binding to microtubules. Results from these studies will provide insights into the cellular mechanisms of anticancer drugs such as taxol, a promising drug that is currently used to treat breast and ovarian cancers, and is in clinical trials for several additional cancers. These studies may not only illuminate basic mechanisms of cellular function but may ultimately point to new strategies for the treatment of human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077317-03
Application #
6173483
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fu, Yali
Project Start
1998-07-24
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$184,649
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Kar, A K; Braun, P D; Wandless, T J (2000) Synthesis and evaluation of daunorubicin-paclitaxel dimers. Bioorg Med Chem Lett 10:261-4