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Triplex Forming Therapeutic Agents for Breast Cancer

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Annual rept. 15 Dec 1992-14 Dec 1993

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The overall goal of this proposal is to develop sequence specific DNA binding compounds which are targeted by triplex DNA formation to the promoters of genes which play an important role in the malignant phenotype of breast carcinoma cells. Our proposal was based largely on our extensive experience with the transcriptional inhibitory effects of G-C specific DNA binding drugs such as mithramycin. All of the test systems and reagents necessary for the proposed experiments were available at the beginning of the funding period, which has allowed us to make substantial progress during the past year. In addition, we have made several unexpected observations which have substantially enhanced the likelihood that this approach will be successful. During the first year of funding of this grant we have established the animal models which we proposed in the original application, we have demonstrated that nebullarine substituted TFOs have markedly increased binding affinity, we have shown that murine targeted acridine-oliognucleotide conjugates have very little, if any, toxicity, and we have been able to demonstrate markedly enhanced antitumor effects of neu- targeted TFOs delivered by liposomes. This progress has encouraged us to push forward with the clinical applications of this work. We are quite confident that within the next year of funding we will be prepared to embark on clinical trials of triplex forming agents in breast cancer.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research
  • Toxicology

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