Butyrate Therapy for Poorly Differentiated Breast Cancer
Abstract
This project aimed to achieve butyric acidemia, and systemic inhibition of histone deacetylase in mice. Tributyrin (butyrate triglyceride) was used as a butyrate prodrug, while methylenecyclopropaneacetate (MCPA) inhibited butyrate metabolism. We monitored physiology and blood chemistry to assure survival during acidosis. Our hypothesis was that maintenance of butyrate blood levels between 1 and 5 mM would yield regression of xenografted tumors corresponding to butyrate hypersensitive breast cancer Previous experience with organicacidemias and hypoglycin (i.e., MCPA) poisoning suggested that prolonged exposure to such acids would lead to bone marrow depression and hair loss, but would be compatible with life. Butyric acidemia was dramatically accentuated by MOPA. However, long duration butyric acidemia was confounded by: 1) intraperitoneal tributyrin emulsion provided variable durations of butyrate release; 2) MCPA inhibition of butyrate catabolism proved limited in duration, and high plasma butyrate interfered with the ability to reattain inhibition by MOPA; and 3) support of blood pH and glucose in individual animals was confounded by low blood volume (relative to instrumentation) and the extended period of critical care required. MOPA had little effect on the antiproliferative effects or deacetylase-inhibitory activity of butyrate in cultured cells. Future studies will compare continuous infusion of monobutyrin/MCPA and deacetylase-inhibitory hydroxamates.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADA388715
Entities
People
- John A. Mcbain
Organizations
- Dartmouth College