Project: Research project

Project Details


DESCRIPTION: (Applicant's Abstract) The long-term objectives of this
application are to acquire a thorough understanding of the mechanisms of
action and of resistance to Taxol, an antitumor agent that is known to be
efficacious in the treatment of human cancer. Knowledge gained from the
studies described in this application will improve the ability to design
Taxol analogs with a better therapeutic index and to develop strategies to
reverse or overcome drug resistance. The understanding of Taxol will be
applied to other natural products such as the epothilones, whose mechanisms
of action and resistance may be similar to that of Taxol. The specific
objectives of this application are to: 1). Define the binding site for
Taxol in the microtubule. Taxol analogs with radiolabeled photoreactive
substituents at defined positions around the taxane nucleus and in the
A-ring sidechain will be used to define the pocket in the microtubule in
which Taxol fits. Each photoreactive substituent will provide another
contact point between the drug and the microtubule. 2). Determine if
modulating the levels of beta-tubulin isotypes in cells can alter
sensitivity to Taxol. Two approaches will be used to analyze this problem;
one involves inducible gene expression with the tetracycline and/or ecdysone
regulated system and the other beta-tubulin antisense oligonucleotides. 3).
Expand the applicant's studies on analyzing alterations in the levels of
beta-tubulin isotypes in human ovarian tumors that acquire Taxol resistance.
4). Investigate endogenous molecules, such as p19, that regulate
microtubule disassembly and may thereby antagonize the activity of Taxol and
modulate low level resistance to the drug. 5). Perform structure activity
relationships (SAR) studies on epothilone analogs to determine the
structural requirements for biological activity. Examine the sensitivity of
Taxol-resistant cells to epothilone and develop epothilone-resistant cells
so that the two drugs can be carefully compared.
Effective start/end date6/1/986/30/21


  • Cancer Research
  • Genetics
  • Medicine(all)
  • Oncology
  • Immunology
  • Cell Biology


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