A profound cytotoxic action of the antimalarial, artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC 50 values) for ART correlated significantly to the cell doubling times (P ϭ 0.00132) and the portion of cells in the G 0 /G 1 (P ϭ 0.02244) or S cell cycle phases (P ϭ 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (ϭ12%) genes correlated significantly to the IC 50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P ϭ 0.00017). For exemplary validation, cell lines transduced with 3 of the 12 genes were used to prove a causative relationship. The cDNAs for a deletion-mutated epidermal growth factor receptor (EGFR) and for ␥-glutamylcysteine synthetase increased resistance to ART. The conditional expression of the CDC25A gene using a tetracycline repressor expression vector increased sensitivity toward ART. Multidrug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent andindependent pathways in isogenic p53ϩ/ϩ p21 WAF1/CIP1 ϩ/ϩ, p53Ϫ/Ϫ p21 WAF1/CIP1 ϩ/ϩ, and p53ϩ/ϩ p21 WAF1/CIP1

The growth of an individual is deeply influenced by the regulation of cell growth and division, both of which also contribute to a wide variety of pathological conditions, including cancer, diabetes, and inflammation. To identify a major regulator of human growth, we performed positional cloning in an autosomal recessive type of profound short stature, anauxetic dysplasia. Homozygosity mapping led to the identification of novel mutations in the RMRP gene, which was previously known to cause two milder types of short stature with susceptibility to cancer, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis. We show that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the cartilage hair hypoplasia founder mutation affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin messenger RNA (mRNA) levels but do severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA while allowing normal mRNA processing and, therefore, genetically separate the different functions of RNase MRP.

Activation of the gp130 signal transducer is mandatory for INA-6 cell growth in vitro and in vivo. Both the MAPK and the Jak/STAT pathway are operative in malignant plasma cells and either one is essential for plasma cell growth. The INA-6 cell line provides a preclinical model to study growth regulation of human plasmacytoma cells and to evaluate novel therapeutic strategies.

No abstract

In extension of a previous study, spontaneous and clastogen-induced chromosome damage was analyzed in cultures of peripheral blood lymphocytes from six further patients with Werner syndrome (WS) and six healthy controls. In addition, sister chromatid exchange (SCE) was estimated in four of these cases. Lymphocytes of patients with various other diseases were used for another series of control experiments. Diepoxybutane (DEB), 4-nitroquinoline-1-oxide (NQO), and bleomycin (BLM) were the standard clastogens throughout the study. While the spontaneous frequency of chromosomal breakage was significantly higher in lymphocytes from all the patients than in the control cells, the basis SCE rate was unaffected in WS cells. Sensitivity of WS cells to the chromosome-damaging action of BLM did not differ from that of control cells, and their sensitivity to DEB was slightly greater than that of control lymphocytes. However, NQO induced a more distinct increase of both break and interchange aberrations in the WS cells than in control cells or cells from patients with other diseases. This effect was not found for the SCE rate. Our data demonstrate the exceptional cytogenetic features of this syndrome: Although the spontaneous and the DEB- and NQO-induced chromosomal breakage rate would suggest that WS is like a classic chromosomal instability syndromes, the lack of sensitivity of WS cells to bleomycin and their stable SCE frequency compared with that of control cells clearly delimitate this syndrome from other entities.