GR-891: a novel 5-fluorouracil acyclonucleoside prodrug for differentiation therapy in rhabdomyosarcoma cells

Differentiation therapy provides an alternative treatment of cancer that overcomes the undesirable effects of classical chemotherapy, i.e. cytotoxicity and resistance to drugs. This new approach to cancer therapy focuses on the development of specific agents designed to selectively engage the process of terminal differentiation, leading to the elimination of tumorigenic cells and recovery of normal cell homeostasis. A series of new anti-cancer pyrimidine acyclonucleoside-like compounds were designed and synthesized by structural modifications of 5-fluorouracil, a drug which causes considerable cell toxicity and morbidity, and we evaluated their applicability for differentiation therapy in human rhabdomyosarcoma cells. We tested the pyrimidine derivative GR-891, (RS)-1-{[3-(2-hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil, an active drug which shows low toxicity in vivo and releases acrolein which is an aldehyde with anti-tumour activity. Both GR-891 and 5-fluorouracil caused time- and dose-dependent growth inhibition in vitro; however, GR-891 showed no cytotoxicity at low doses (22.5 μmol l−1 and 45 μmol l−1) and induced terminal myogenic differentiation in RD cells (a rhabdomyosarcoma cell line) treated for 6 days. Changes in morphological features and in protein organization indicated re-entry in the pathway of muscular maturation. Moreover, GR-891 increased adhesion capability mediated by the expression of fibronectin, and did not induce overexpression of P-glycoprotein, the mdr1 gene product, implicated in multidrug resistance. New acyclonucleoside-like compounds such as GR-891 have important potential advantages over 5-fluorouracil because of their lower toxicity and their ability to induce myogenic differentiation in rhabdomyosarcoma cells. Our results suggest that this drug may be useful for differentiation therapy in this type of tumour. 1999 Cancer Research Campaig

A sequence downstream of AAUAAA is required for rabbit beta-globin mRNA 3'-end formation.

The sequence AAUAAA, found 11-30 base pairs (bp) upstream of the poly(A) site of most non-histone eukaryotic messenger RNAs (mRNAs) forms an essential part of the recognition site for 3'-end processing of the primary transcript. However, the sequence AATAAA is found in transcribed regions of genes and is differentially utilized in genes containing multiple copies of the sequence within the 3'-noncoding region, suggesting that the hexanucleotide alone does not comprise a complete recognition site. Therefore, it seems likely that additional sequences are required to form a complete recognition site for 3'-end formation. We have investigated the sequence requirements for mRNA 3'-end formation using the rabbit beta-globin gene as a model system. Here we demonstrate that an additional sequence 3' to AAUAAA is required for the correct 3'-end formation of rabbit beta-globin mRNA