A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year ( with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months ( patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 mug of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies

The transcription factor NF-κB in the demosponge Amphimedon queenslandica : insights on the evolutionary origin of the Rel homology domain

The Rel/nuclear factor-kappa B (NF-κB) and nuclear factor of activated T-cells (NFAT) transcription factors contribute to the regulation of an assortment of biological processes by binding DNA with high specificity using their Rel homology domain (RHD). Recently, it has been shown that members of these gene families are present in the genome of the anthozoan cnidarian Nematostella vectensis, indicating that they predate the evolution of the most recent ancestor to living bilaterians. By identifying a single NF-κB gene in the genome of the demosponge Amphimedon queenslandica, a representative of an even earlier branching metazoan lineage, we demonstrate here that the Rel/NF-κB family originated at the dawn of the Metazoa. There is no evidence of RHDs in fungal and choanoflagellate genomes, supporting the notion that the RHD is a metazoan-specific innovation. The A. queenslandica gene (AmqNF-κB) encodes a protein that is highly similar in structure to the vertebrate NF-κB p50/p52 proteins, possessing both a RHD and ankyrin (ANK) repeats. The intact AmqNF-κB contrasts with the N. vectensis NF-κB, which lacks ANK repeats, and suggests that the ancestral metazoan NF-κB was configured identically to contemporary vertebrate and sponge forms. AmqNF-κB is expressed during A. queenslandica embryogenesis, suggesting a developmental role