New Drugs for Prevention of Breast Cancer Metastases.
Abstract
This project has as its basis the discovery in my laboratory of a unique growth-related protein at the external cell surface. The protein, designated tNOX, is an anti-tumor drug-responsive hydroquinone (NADH) oxidase with protein disulfide-thiol interchange activity. In metastasis models, tNOX inhibitors prevent the invasive spread of cancer. The present project was to develop one or more lead drugs to prevent metastases in a breast cancer model. Glaucarubolone, a natural product tNOX inhibitor, both free and conjugated to polyethylene-glycol 5000, was prepared in quantities sufficient for animal testing. The EC 50 for the glaucarubolone on the growth of 4T1 mouse mammary carcinoma cells was determined to be > 1 %M. That for the conjugate was < 1 %M. Free glaucarubolone supplied intra-tumorally to mice bearing transplanted mammary carcinomas was toxic and ineffective in the prevention of the formation of lung metastases. The conjugate was not toxic and a response was seen at the highest concentration tested of 5 mg/injection/mouse. In a collagen invasion assay, the glaucarubolone-PEG conjugate was effective at concentrations between 10.8 and 10.10 M. The conjugate will be redesigned to improve solubility and intra-tumor distribution to facilitate attainment of therapeutic doses.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADA356194
Entities
People
- James D. Morre
Organizations
- Purdue Research Foundation