Butyrate Therapy for Poorly Differentiated Breast Cancer
Annual rept. 15 Sep 97-14 Sep 98
DARTMOUTH COLL HANOVER NH
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This research program is directed at providing a 24 hr regimen of butyric acidemia which exceeds 5 mM butyrate while remaining below 5mM. Work to date has shown that appropriate dose schedules of treatment with methylenecyclopropane acetic acid can inhibit butyrate catabolism sufficient for this end. The inhibition effected by MCPA has been shown to be both transitory and suppressed by high concentrations of butyrate, suggestive of some challenging pharmacological interactions between MCPA and butyrate. Butyrate free from exogenous counterion is shown to be available from tributyrin, although the water insolubility of tributyrin limits its usefulness. Mice have been found to tolerate butyrate concentrations as high as 58 mM and accompanying pHs as low as 6.9. The metabolic acidosis and hypoglycemic sequelae require incremental correction with bicarbonate and glucose, while MCPA-induced hypothermia requires temperature control of housing. The goal of these studies is the demonstration of histone hyperacetylation in the tissues of these mice, and then whether human breast cancer cell line xenografts can be selectively caused to regress. It is anticipated that our goals will be met by a combination of continuous infusion of monobutyrin from which butyrate is freely available to animals which are initially pretreated with MCPA, and then provided MCPA as a continuous supplement.
- Medicine and Medical Research
- Organic Chemistry