INHIBITION OF DNA REPAIR TO ENHANCE CHEMOTHERAPY

  • Pegg, Anthony (PI)
  • Gerson, Stanton (PI)
  • Friedman, Henry S. (PI)
  • Schold, S. (PI)
  • Dolan, M. Eileen (PI)

Project: Research project

Description

There is compelling evidence indicating that the presence in tumor cells of
the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, imparts
resistance to chemotherapeutic chloroethylating and methylating agents.
This proposal has as its main themes the development of ways to minimize
this resistance and exploitation of the absence of this activity to
increase the general effectiveness of these agents. The experiments will
address several questions needed to achieve this objective and will focus
on: (a) testing whether O6-benzylguanine is a useful agent for this
purpose; (b) developing other alkyltransferase inactivators that may have
greater potency or better selectivity towards tumor cells than O6-
benzylguanine; (c) examining alternative methods of reducing
alkyltransferase levels and testing the regulation of alkyltransferase
levels in response to inhibitors and therapeutic agents; and (d) studying
the distribution of alkyltransferase in tumors to provide a method to
identify those tumors for which alkyltransferase inactivation will be
beneficial. There are 6 programs. Dr. A.E. Pegg will serve as the
Principal Investigator and the Leader of Program 1 which will carry out
biochemical studies to design, synthesize and test compounds which
inactivate the alkyltransferase. Dr. R.C. Moschel will serve as a
collaborator for this section and will synthesize compounds as
alkyltransferase inhibitors. Dr. M.E. Dolan will serve as the leader of
Program 2 and will examine the metabolic stability and uptake of these
inhibitors and test their effects on the response of melanomas and lung
tumors to alkylating agents. In Program 3, Dr. D.B. Yarosh will use
immunohistochemical techniques to study the distribution of
alkyltransferase in tumors and the response to inhibitors and chemotherapy.
He will also investigate whether an antisense approach to reduction of the
alkyltransferase levels is valuable. In program 4, Dr. L.C. Erickson will
investigate the regulation of the alkyltransferase levels and the synergism
between treatments involving chloroethylating agents, streptozotocin and
depletion of alkyltransferase. In program 5, Dr. S.L. Gerson will test the
efficacy of inhibiting alkyltransferase as a means to enhance the
chemotherapeutic effectiveness of alkylating agents against breast cancer.
He will also investigate methods to protect normal myeloid cells and
precursors. In program 6, Drs. S.C. Schold and H. Friedman will study the
use of alkyltransferase inactivation in improving the therapy of brain
tumors by alkylating agents and test whether intrathecal administration of
the inhibitors improves the therapeutic efficacy.
StatusFinished
Effective start/end date8/17/929/29/01

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $926,421.00
  • National Institutes of Health
  • National Institutes of Health: $1,498.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $649,716.00
  • National Institutes of Health: $737,618.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $686,872.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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DNA Repair
Alkyl and Aryl Transferases
Carmustine
Drug Therapy
Neoplasms
Prodrugs
Colon
Cell Culture Techniques
Alkylating Agents
Breast Neoplasms
Proteins
Prostate
Substrates
Therapeutics
temozolomide
Carcinoma
Escherichia coli
Lung
Enzymes
Methylnitronitrosoguanidine