Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease.

High levels of fetal hemoglobin (Hb F) protect from many of the complications of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrates are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.

The anti-proliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells: alterations in tumor suppressor and cell cycle-regulatory proteins.

Nonsteroidal anti-inflammatory drugs lower the incidence of and mortality from colon cancer. Sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. We have shown that sulindac and sulindac sulfide reversibly reduce the proliferation rate of HT-29 colon cancer cells, alter their morphology, induce them to accumulate in the G0/G1 phase of the cell cycle, and sulindac sulfide induces cell death by apoptosis. In this study we confirmed that sulindac and sulindac sulfide prevent HT-29 cells from progressing from the G0/G1 into the S phase. This block in cell cycle progression is associated with an initial rise, then an abrupt decrease in the levels of p34cdc2 protein. Sulindac and sulindac sulfide decrease the levels of mitotic cyclins, induce the levels of p21WAF-1/cip1, and reduce the total levels of pRB, with a relative increase in the amount of the underphosphorylated form of pRB in a time- and concentration-dependent manner. In addition, these compounds reduce the levels of mutant p53. These responses are not associated with intestinal cell differentiation and occur independent of the ability of these compounds to induce apoptosis. We conclude that sulindac and sulindac sulfide reduce the levels of major components of the molecular cell cycle machinery and alter the levels of several tumor suppressor proteins in a manner consistent with cell cycle quiescence. These mechanisms may be operative in vivo to account, in part, for the anti-neoplastic effects of these compounds.