DCA and CancerDCA as a Cancer Treatment - Sodium Dichloroacetate

Phase I and Pharmacokinetic Study of Tributyrin: a Butyrate Prodrug and Possible Inhibitor of Histone Deacetylase.

Sub-category: Phase I Trials
Category: Clinical Pharmacology
Meeting: 2001 ASCO Annual Meeting

Abstract No: 342
Citation: Proc Am Soc Clin Oncol 20: 2001 (abstr 342)
Author(s): Shyam L. Khanwani, Martin J. Edelman, Nancy Tait, Kenneth Bauer, Laxmi Buddharaju, Bijoyesh Mookerjee, David Van Echo, Judith E. Karp, University of Maryland Greenebaum Cancer Center, Baltimore, MD.

Abstract: Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 500 mM.

We demonstrated that oral administration of the prodrug, tributyin, was able to briefly achieve levels 500 mM with daily administration (Clin Ca Res 629-34, 1998). This led us to evaluate a tid schedule. In addition, recent data indicates that inhibition of histone deacetylation is potentially an important mechanism of action for butyrate, therefore, we assessed histone acetylation before and after administration of tributyrin.

Patients and Methods: 28 patients with advanced solid tumors for whom no other therapy was available and had life expectancy 12 wks and nl organ function were enrolled and treated with tributyrin at doses from 50 mg/kg qd to 200 mg/kg tid (see definition below). Blood was sampled for pK at 0,15,30 min and q1hx4. Protein was isolated from peripheral blood lymphocytes obtained prior to therapy and at d 1,2,15,16 to assess for histone acetylation by western blot. Demographics: 22 M/9F, 19W/10 AA/1 other. Median age: 61 y (range 30-74). Prior therapy: chemotherapy: 26 (median 2 prior regimens, range 1-5), XRT- 2, no prior therapy:

3. Toxicity: There was no dose limiting toxicity. 3 patients had Grade III nausea/vomiting (none at the highest dose levels), 1 patient had Gr III myalgias. Pk : At the tid dosing schedule (n=14) preliminary data indicate that levels 500 mM are routinely obtainable. Response: No objective responses were seen. There were six patients with prolonged disease stabilization ranging from 3-23 months, median progression free survival was 57 days. Levels of histone acetylation are pending.

Conclusions: Tributyrate is well tolerated and levels associated with in vitro activity are easily achieved with tid dosing. We are currently assessing the ability of this agent to inhibit histone deacetylation. Supported by U01 CA 69854

Treatment schedule definitions: (from http://clincancerres.aacrjournals.org/cgi/reprint/11/20/7499.pdf)
once daily (q.d.)
(thrice a day, t.i.d.
every other day, q.o.d
every 3rd day, q.3.