Synthesis and antiprotozoal activity of mono- and bis-uracil isatin conjugates against the human pathogen Trichomonas vaginalis.

A library of mono- and bis-uracil isatin conjugates were synthesized and subjected for the assessment of their in vitro activity against the protozoal pathogen Trichomonas vaginalis. The structure activity studies (SAR) revealed that the bis-uracil-isatin based conjugates were more effective than their corresponding mono conjugates in inhibiting the growth of T. vaginalis at approximately 10 µM with no visual effect on mammalian cells at the same concentration.

Cdx1 inhibits the proliferation of human colon cancer cells by reducing cyclin D1 gene expression.

The transcription factor Cdx1 regulates intestine-specific gene expression and enterocyte differentiation. It has been hypothesized to play a role in regulating intestinal cell proliferation; however, the mechanism for this effect remains elusive. In a prior study, we demonstrated that Cdx1 expression reduced the proliferation of a nontransformed intestinal cell line. This study tests the hypothesis that Cdx1 expression inhibits colon cancer cell proliferation by reducing cyclin D1 gene expression. Cdx1 expression markedly reduced cancer cell proliferation and DNA synthesis and induced an accumulation of cells in G0/G1. A transcriptionally inactive Cdx1 mutant could not elicit this effect, suggesting that it required Cdx1 transcriptional activity. Cdx1 expression increased the hypophosphorylation of the retinoblastoma (pRb) and p130 proteins. Reductions in G1 cyclin-dependant kinase (cdk) activity accompanied this effect. Cyclin D1 mRNA and protein levels were diminished by Cdx1 expression. Restoration of cyclin D1 expression reversed the G0/G1 block and induced pRb hyperphosphorylation. Lastly, Cdx1 expression did not alter cyclin D1 mRNA stability but did reduce cyclin D1 promoter activity, suggesting that Cdx1 acts to diminish cyclin D1 gene transcription. We conclude that Cdx1 reduces the proliferation of human colon cancer cells by reducing cyclin D1 gene transcription.

Raloxifene and colorectal cancer.

OBJECTIVE: To determine the effect of raloxifene on colorectal cancer (CRC) risk. METHODS: We analyzed data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a randomized, blinded clinical trial designed to determine the effect of raloxifene on vertebral fracture risk. In this trial, 7705 women received either raloxifene or placebo and were followed for an average of 3.4 years. CRC cases were classified as definite (pathology available), probable (imaging or colonoscopic diagnosis), or possible (self-report). Relative hazard for CRC was calculated using multivariate Cox proportional hazards models. RESULTS: Fifty cases of definite or probable CRC were diagnosed; 40 were definite and 10 probable. Twenty-nine cases occurred among the 5129 women in the raloxifene group, and 21 occurred among the 2576 women in the placebo group (p = 0.15). The relative hazard for CRC for women treated with raloxifene was 0.78 (95% CI 0.43, 1.43, p = 0.43). Restricting the analysis to definite CRC, the relative hazard was 0.77 (95% CI 0.39, 1.5, p = 0.45). CONCLUSIONS: Although the MORE trial was large, the number of CRC cases was too small to provide definitive evidence concerning the effect of raloxifene on CRC risk. There does not appear to be a substantial increased risk of CRC with raloxifene use. Studies including larger numbers of women and women at risk for CRC should further investigate the effect of raloxifene on CRC.