Resistance to chemotherapy is a major obstacle in the treatment of cancer. Despite the advent of new chemotherapies and molecular-targeted therapies, approximately 90% of patients with metastatic cancer succumb to their disease. Drug resistance, either acquired or intrinsic, often prevents tumour cells from undergoing sufficient levels of programmed cell death or apoptosis, resulting in cancer cell survival and treatment failure. In pre-clinical disease models, agents that target the apoptotic pathway have been shown to sensitize tumour cells to chemotherapy and radiotherapy. Such therapies include small molecule inhibitors and antisense strategies that inhibit the activity of anti-apoptotic proteins, or treatment with recombinant pro-apoptotic proteins or antibodies that can activate the apoptotic pathway. This review will discuss apoptosis and the mechanisms by which it can become dysregulated in human cancer. In addition, novel therapeutic strategies that target key components of the apoptotic machinery will be discussed.
In this study we test the theory that the presence of the conserved vertebrate telomeric sequence (T(2)AG(3))(n) at the centromeres of Australian marsupial 2n = 14 complements is evidence that these karyotypes are recently derived, which is contrary to the generally held view that the 2n = 14 karyotype is ancestral for Australasian and American marsupials. Here we compare the distribution of the (T(2)AG(3))( n ) sequence and constitutive heterochromatin in the presumed ancestral 2n = 14 complement and in complements with known rearrangements. We found that where there were moderate to large amounts of constitutive heterochromatin, the distribution of the (T(2)AG(3))(n) sequence reflected its presence as a native component of satellite DNA rather than its involvement in past rearrangements. The presence of centromeric heterochromatin in all Australian 2n = 14 complements therefore suggests that centromeric sites of the (T(2)AG(3))(n) sequence do not represent evidence for recent rearrangements.
SummaryThe primary element in the cAMP signal transduction pathway is the cAMP-dependent protein kinase (PKA). Expression of the RIα subunit of type I PKA is elevated in a variety of human tumours and cancer cell lines. The purpose of this study was to assess the prognostic importance of RIα expression in patients with ovarian cancer. We have evaluated the expression of RIα in a panel of human ovarian tumours (n = 40) and five human ovarian cancer cell lines using quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. The human ovarian cell lines OAW42 and OTN14 express high endogenous levels of RIα mRNA and protein (at significantly higher mRNA levels than high tissue expressors, P < 0.05). The ovarian cell line A2780 expresses low endogenous levels of RIα mRNA and protein (also at higher mRNA levels than low tissue expressors, P < 0.05). Quantitative RT-PCR revealed no significant difference in RIα mRNA expression between different ovarian histological subtypes in this study. No associations were found between RIα mRNA expression and differentiation state. RIα mRNA expression was significantly associated with tumour stage (P = 0.0036), and this remained significant in univariate analysis (P = 0.0002). A trend emerged between RIα mRNA expression levels and overall survival in univariate analysis (P = 0.051), however, by multivariate analysis, stage remained the major determinant of overall survival (P = 0.0001). This study indicates that in ovarian epithelial tumours high RIα mRNA expression is associated with advanced stage disease. RIα expression may be of predictive value in ovarian cancer and may be associated with dysfunctional signalling pathways in this cancer type.
A significant proportion of human cancers overexpress DNA polymerase beta (Pol b), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol b, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol b protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol b protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol b delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol b-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol b-expressing cells. Consistent with previous studies, Pol b-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol b. They demonstrate that Pol b modulates the sensitivity of cells to oxaliplatin treatment.
This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress.
Expression of the sex-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) was examined electrophoretically in tissues and cultured fibroblasts of female kangaroo heterozygotes ranging in age from 26 days post part urn to adult. All tissues expressed only the maternally derived allele irrespective of which allele was maternal or paternal in origin.By contrast, cultured fibroblasts derived from these same heterozygotes displayed unique G6PD phenotypes not found in the living animal. These phenotypes consist of a broad. band which either completely or partially overlaps the allozymes produced by the maternally and paternally derived alleles. In vitro hybridization of G6PD from species showing greater differences in electrophoretic mobility indicate that G6PD is a dimer in marsupials. The cultured fibroblast G6PD phenotypes are consistent with different proportions of homodimer and heterodimer formation. The appearance of the heterodimer indicates that both alleles are active within the one cell. This conclusion is reinforced by the finding that clones from cultured fibroblasts of one of the heterozygotes had an identical phenotype to that of the mass culture from which the clones were derived.It is concluded that some heterozygotes express both Gpd alleles equally in each cultured fibroblast while other heterozygotes show normal activity of the maternally derived allele and partial expression of the paternally derived allele.
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