Surgery 1998 Aug;124(2):248-53
Butyrate inhibits colon carcinoma cell growth through two distinct
pathways.
Archer S, Meng S, Wu J, Johnson J, Tang R, Hodin R
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA.
BACKGROUND: Dietary fiber and the resultant increase in colonic butyrate levels protect against colon carcinogenesis.
Previous studies have shown that p21 and histone hyperacetylation are important in basal growth inhibition by butyrate. This
study was designed to elucidate other mechanism underlying the butyrate effects on cell growth. METHODS: HT-29 colon
carcinoma cells (standard medium or medium lacking serum) were treated with sodium butyrate (NaBu), epidermal growth
factor (EGF), or both. Northern blot analyses were performed with cDNA probes specific for c-fos, c-jun, and actin. Cell
growth was measured by 3H-thymidine incorporation. Enzyme-linked immunosorbent assay (ELISA) was used to quantify
EGF receptor levels. RESULTS: Butyrate and serum starvation (SS) both induced a cell cycle withdrawal by 24 hours. In
response to EGF treatment, SS cells exhibited a growth spurt and induced c-fos and c-jun proto-oncogene expression,
whereas butyrate-treated cells exhibited minimal growth response to EGF. This relative unresponsiveness to EGF in
butyrate-treated cells corresponded to a dramatic decline in EGF receptor levels when compared to untreated controls.
CONCLUSIONS: Butyrate appears to inhibit colon cancer cell growth by two mechanisms, one involving histone
hyperacetylation and p21 induction and the other related to impaired EGF-responsiveness.
Oncol Res 1998;10(2):75-84
Potentiation of retinoic acid-induced differentiation of human acute
promyelocytic leukemia NB4 cells by butyric acid, tributyrin, and
hexamethylene bisacetamide.
Taimi M, Chen ZX, Breitman TR
Laboratory of Biological Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255,
USA.
Cytodifferentiation therapy by all-trans-retinoic acid (RA) for acute promyelocytic leukemia patients is encouraging in spite of
several limitations preventing better clinical outcomes. Most patients in complete remission induced by RA experience relapse
and resist further treatment with RA. This resistance primarily is due to a systemic self-induced catabolism of RA, which
interferes with the maintenance of effective plasma levels of RA. In this report we explored the possibility that treatment with
combinations of RA and other differentiation agents may induce differentiation at lower RA concentrations, which in turn may
produce diminished levels of resistance. We found that although n-butyric acid (BA), tributyrin (TB) (a prodrug of BA), or
hexamethylene bisacetamide (HMBA) were inactive as sole agents they potentiated RA-induced differentiation of human acute
promyelocytic NB4 cells. A measure of the effectiveness of these combinations was that the concentrations of RA in
combination with BA and HMBA inducing half-maximal differentiation were 20- to 40-fold lower than those needed with RA
alone. Furthermore, the concentrations of BA and HMBA in these combinations were at achievable plasma levels. Therefore,
these combinations may have clinical utility for treatment of a variety of malignancies that are sensitive to RA alone.
Clin Cancer Res 1998 Mar;4(3):629-34
Phase I study of the orally administered butyrate prodrug, tributyrin, in
patients with solid tumors.
Conley BA, Egorin MJ, Tait N, Rosen DM, Sausville EA, Dover G, Fram RJ, Van Echo DA
Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.
Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a
triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a
number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We
treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an
overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses
without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose
escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea,
headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor,
dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate
concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak
concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on
days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate
disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a
dose of 450 mg/kg/day. |
