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Biomedical subjects

Per Eystein Lønning

Publications and source records attributed to Per Eystein Lønning.

At least 19 recordsLinked to original sources
PubMed2006

The novel p21 polymorphism p21G251A is associated with locally advanced breast cancer.

PURPOSE: p21 is a main effector of growth arrest induced by p53. In addition, a second transcript from the same gene (p21B) has been linked to apoptosis. We previously analyzed p21 status in breast cancer and reported two novel polymorphisms of the p21 gene. In the present study, we present a larger study designed to explore a possible association between these novel polymorphisms and breast cancer. EXPERIMENTAL DESIGN: The p21/p21B polymorphisms were analyzed in 507 breast cancer patients and 1,017 healthy individuals using cDNA or genomic DNA from tumor and/or blood samples. RESULTS: We detected five polymorphisms of the p21 gene. Three of these polymorphisms are earlier reported by others, whereas two were reported for the first time in a recent study by us. The presence of the A allele of the p21G251A polymorphism was observed more frequently among patients with primary stage III breast cancer (4.5%) compared with stage I and II tumors (1.5%) and healthy female controls (1.4%; P = 0.007, comparing the three groups; P = 0.0049 and P = 0.0057, comparing locally advanced to stage I/II and healthy controls, or to healthy controls alone, respectively). The allele frequencies of the remaining four polymorphisms were evenly distributed among patients and healthy individuals. DISCUSSION: The finding of an association between locally advanced breast cancer and one particular polymorphism of the p21 gene suggests this polymorphism to be related to tumor behavior, including enhanced growth rate. If confirmed in other studies, this may add significant information to our understanding of the biology as well as of the clinical behaviour of locally advanced breast cancers.

Breast Neoplasms↗
PubMed2006

Promyelocytic leukemia nuclear bodies are predetermined processing sites for damaged DNA.

The promyelocytic leukemia protein (PML) participates in several cellular functions, including transcriptional regulation, apoptosis and maintenance of genomic stability. A key feature of this protein is its ability to induce the assembly of nuclear compartments termed PML-nuclear bodies (PML-NBs). Here we show that these nuclear structures recruit single-stranded DNA (ssDNA) molecules in response to exogenous DNA damage. ssDNA was readily detected in PML-NBs within 1 hour following exposure of cells to UV light. Confocal real-time imaging of cells expressing YFP-tagged PML did not reveal de novo formation of new PML-NBs following UV-irradiation, which shows that ssDNA focus formation occurred within pre-existing PML-NBs. Moreover, siRNA-mediated depletion of PML prevented ssDNA focus formation and sensitized cells to UV-induced apoptosis. PML-dependent ssDNA focus formation was found to be particularly efficient during S-phase of the cell cycle, and PML-depleted cells became retarded in S-phase upon growth in the presence of etoposide. In addition, we found that caffeine and the poly(ADP-ribose) polymerase (PARP) inhibitor NU1027 enhanced UV-induced recruitment of ssDNA to PML-NBs. Together, our results show that PML-NBs have the capacity to accommodate DNA metabolic activities that are associated with processing of damaged DNA.

Apoptosis↗
PubMed2006

Genetic variation in putative regulatory loci controlling gene expression in breast cancer.

Candidate single-nucleotide polymorphisms (SNPs) were analyzed for associations to an unselected whole genome pool of tumor mRNA transcripts in 50 unrelated patients with breast cancer. SNPs were selected from 203 candidate genes of the reactive oxygen species pathway. We describe a general statistical framework for the simultaneous analysis of gene expression data and SNP genotype data measured for the same cohort, which revealed significant associations between subsets of SNPs and transcripts, shedding light on the underlying biology. We identified SNPs in EGF, IL1A, MAPK8, XPC, SOD2, and ALOX12 that are associated with the expression patterns of a significant number of transcripts, indicating the presence of regulatory SNPs in these genes. SNPs were found to act in trans in a total of 115 genes. SNPs in 43 of these 115 genes were found to act both in cis and in trans. Finally, subsets of SNPs that share significantly many common associations with a set of transcripts (biclusters) were identified. The subsets of transcripts that are significantly associated with the same set of SNPs or to a single SNP were shown to be functionally coherent in Gene Ontology and pathway analyses and coexpressed in other independent data sets, suggesting that many of the observed associations are within the same functional pathways. To our knowledge, this article is the first study to correlate SNP genotype data in the germ line with somatic gene expression data in breast tumors. It provides the statistical framework for further genotype expression correlation studies in cancer data sets.

Breast Neoplasms↗
PubMed2006

Evaluation of MetriGenix custom 4D arrays applied for detection of breast cancer subtypes.

BACKGROUND: Previously, a total of five breast cancer subtypes have been identified based on variation in gene expression patterns. These expression profiles were also shown to be associated with different prognostic value. In this study tumour samples from 27 breast cancer patients, previously subtyped by expression analysis using DNA microarrays, and four controls from normal breast tissue were included. A new MetriGenix 4D array proposed for diagnostic use was evaluated. METHODS: We applied MetriGenix custom 4D arrays for the detection of previously defined molecular subtypes of breast cancer. MetriGenix 4D arrays have special features including probe immobilization in microchannels with chemiluminescence detection that enable shorter hybridization time. RESULTS: The MetriGenix 4D array platform was evaluated with respect to both the accuracy in classifying the samples as well as the performance of the system itself. In a cross validation analysis using "Nearest Shrunken Centroid classifier" and the PAM software, 77% of the samples were classified correctly according to earlier classification results. CONCLUSION: The system shows potential for fast screening; however, improvements are needed.

Breast Neoplasms↗
PubMed2006

Multilocus analysis of SNP and metabolic data within a given pathway.

BACKGROUND: Complex traits, which are under the influence of multiple and possibly interacting genes, have become a subject of new statistical methodological research. One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common multifactorial diseases and their association to different quantitative phenotypic traits. RESULTS: Two types of data from the same metabolic pathway were used in the analysis: categorical measurements of 18 SNPs; and quantitative measurements of plasma levels of several steroids and their precursors. Using the combinatorial partitioning method we tested various thresholds for each metabolic trait and each individual SNP locus. One SNP in CYP19, 3UTR, two SNPs in CYP1B1 (R48G and A119S) and one in CYP1A1 (T461N) were significantly differently distributed between the high and low level metabolic groups. The leave one out cross validation method showed that 6 SNPs in concert make 65% correct prediction of phenotype. Further we used pattern recognition, computing the p-value by Monte Carlo simulation to identify sets of SNPs and physiological characteristics such as age and weight that contribute to a given metabolic level. Since the SNPs detected by both methods reside either in the same gene (CYP1B1) or in 3 different genes in immediate vicinity on chromosome 15 (CYP19, CYP11 and CYP1A1) we investigated the possibility that they form intragenic and intergenic haplotypes, which may jointly account for a higher activity in the pathway. We identified such haplotypes associated with metabolic levels. CONCLUSION: The methods reported here may enable to study multiple low-penetrance genetic factors that together determine various quantitative phenotypic traits. Our preliminary data suggest that several genes coding for proteins involved in a common pathway, that happen to be located on common chromosomal areas and may form intragenic haplotypes, together account for a higher activity of the whole pathway.

Aged↗
PubMed2006

Adeno-associated virus (AAV) serotypes 2, 4 and 5 display similar transduction profiles and penetrate solid tumor tissue in models of human glioma.

BACKGROUND: Adeno-associated viral (AAV) vectors are potent delivery vehicles for gene transfer strategies directed at the central nervous system (CNS), muscle and liver. However, comparatively few studies have described AAV-mediated gene transfer to tumor tissues. We have previously demonstrated that while AAV2 and Adenoviral (Ad) 5 vectors have similar broad host ranges in tumor-derived cell lines, AAV2 was able to penetrate human glioblastoma biopsy spheroids and xenografts more efficiently than Ad 5 vectors. These results suggested that AAV vectors could be suitable for therapeutic gene delivery to solid tumor tissue. In the present work, the transduction efficacy of AAV serotypes 4 and 5 were compared to AAV2, both in vitro and in intracranial GBM xenografts derived from patient biopsies implanted into nude rats. METHODS: AAV vector serotypes 2, 4, and 5 containing either the green fluorescent protein (GFP) or the bacterial beta-galactosidase (lacZ) reporter gene were added to five different human glioma cell lines, to multicellular spheroids generated from glioblastoma patient biopsies, and to spheroids xenografted intracranially in nude rats. Transduction efficiency was assessed by fluorescence imaging, histochemistry, immunohistochemistry and flow cytometry. RESULTS: While all three AAV serotypes were able to transduce the glioma cell lines when added individually or when they were administered in concert, AAV2 transduced the glioma cells most effectively compared to AAV4 or AAV5. Upon infecting glioblastoma spheroids in vitro, all three AAV serotypes efficiently transduced cells located at the surface as well as within deeper layers of the spheroids. In addition, similarly to what was observed for AAV2 16, both AAV4 and AAV5 were able to transduce human glioblastoma xenografts implanted intracranially. CONCLUSIONS: In addition to the widely used AAV2 serotype, AAV4 and AAV5 serotypes may also be used to transduce biologically diverse glioma cell lines. They also penetrate and transduce solid human tumor tissue derived from patient biopsies. Therefore, the data presented here provide a proof of principle for developing AAV4 and AAV5 as treatment vehicles for human malignant gliomas.

Animals↗
PubMed2006

Gene expression profiles do not consistently predict the clinical treatment response in locally advanced breast cancer.

Neoadjuvant treatment offers an opportunity to correlate molecular variables to treatment response and to explore mechanisms of drug resistance in vivo. Here, we present a statistical analysis of large-scale gene expression patterns and their relationship to response following neoadjuvant chemotherapy in locally advanced breast cancers. We analyzed cDNA expression data from 81 tumors from two patient series, one treated with doxorubicin alone (51) and the other treated with 5-fluorouracil and mitomycin (30), and both were previously studied for correlations between TP53 status and response to therapy. We observed a low frequency of progressive disease within the luminal A subtype from both series (2 of 36 versus 13 of 45 patients; P = 0.0089) and a high frequency of progressive disease among patients with luminal B type tumors treated with doxorubicin (5 of 8 patients; P = 0.0078); however, aside from these two observations, no other consistent associations between response to chemotherapy and tumor subtype were observed. These specific associations could possibly be explained by covariance with TP53 mutation status, which also correlated with tumor subtype. Using supervised analysis, we could not uncover a gene profile that could reliably (>70% accuracy and specificity) predict response to either treatment regimen.

Adult↗
PubMed2006

Antitumor efficacy improved by local delivery of species-specific endostatin.

OBJECT: Conflicting results have been reported concerning the antitumor efficacy of the angiogenesis inhibitor endostatin. This may be due to differences in the biological distribution of endostatin between studies or to the varying biological efficacies of the different protein forms that were examined. To address this issue, the authors used a local delivery approach in which each tumor cell secreted endostatin, providing uniform endostatin levels throughout the tumors. This allowed a direct assessment of the biological efficacy of soluble endostatin in vivo. METHODS: The authors genetically engineered BT4C gliosarcoma cells so that they would stably express and secrete either the human or murine form of endostatin. Endostatin-producing cells or mock-infected cells were implanted intracerebrally in syngeneic BD-IX rats. The antitumor efficacy of endostatin was evaluated on the basis of survival data and tumor volume comparisons. In addition, microvascular parameters were assessed. The authors confirmed the continuous release of endostatin by the BT4C cells. A magnetic resonance imaging-assisted comparison of tumor volumes revealed that local production of murine endostatin significantly inhibited tumor growth. Notably, 40% of the animals in this treatment group experienced long-term survival without histologically verifiable tumors 7 months after cell implantation. After local treatment with murine endostatin, tumor blood plasma volumes were reduced by 71%, microvessel density counts by 84%, and vascular area fractions by 75%. In contrast, human endostatin did not inhibit tumor growth significantly in this model. Centrally located regions of necrosis were present in tumors secreting both the human and the murine species-specific form of endostatin. CONCLUSIONS: The results suggest that endostatin inhibits tumor angiogenesis in vivo in a species-specific manner.

Amino Acid Sequence↗
PubMed2005

Aromatase inhibition: translation into a successful therapeutic approach.

The development of the novel third-generation aromatase inhibitors and inactivators for breast cancer treatment is one of the most successful contemporary achievements in cancer therapy. Parallel to studies evaluating toxicity and clinical efficacy in metastatic disease, the endocrine effects of multiple compounds were evaluated, leading to the identification of the highly potent third-generation aromatase inhibitors based on estrogen deprivation and aromatase inhibition in vivo. Thus, translational studies have been of vital importance identifying the unique characteristics of these compounds. Whereas first- and second-generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, the third-generation compounds anastrozole, exemestane, and letrozole were found to cause > or =98% aromatase inhibition. This article summarizes and discusses the "translational research" that provided the background for the implementation of the third-generation aromatase inhibitors and inactivators into large clinical trials. The need for future translational research exploiting the mechanisms of resistance to these compounds for future improvement of endocrine therapy is emphasized.

Anastrozole↗
PubMed2005

[Aromatase inhibitors in the therapy for breast cancer].

BACKGROUND: Endocrine therapy plays a key role in the treatment of breast cancer. Because of high efficacy and low toxicity, endocrine therapy is the first-line treatment of advanced pre- as well as post-menopausal breast cancer. In the adjuvant setting, endocrine therapy has a more profound effect on survival compared to chemotherapy in postmenopausal women harboring receptor positive tumors. NEW THERAPEUTIC MODALITIES: The introduction of the novel third-generation aromatase inhibitors is the most important improvement in endocrine therapy since the introduction of tamoxifen 20 years ago. Thus, phase III studies have shown improved efficacy of these compounds compared to conventional therapy at relapse. Based on preliminary results from large phase III studies, aromfase inhibitors are now to be implemented as adjuvant therapy for postmenopausal women. FUTURE PERSPECTIVES: The uncertainties relate to which drug should be used, regimen (monotherapy or sequential treatment with tamoxifen), and potential toxic effects related to long-term oestrogen deprivation.

Antineoplastic Agents↗
PubMed2005

Endocrine effects of aromatase inhibitors and inactivators in vivo: review of data and method limitations.

The so-called "third-generation" aromatase inhibitors/inactivators have become standard first-line endocrine therapy for postmenopausal women in the metastatic setting. In addition, these compounds, administered as monotherapy or in sequence with tamoxifen, are likely to become standard adjuvant therapy in most countries in the near future. In contrast to the SERMs, aromatase inhibitors may be assessed for their biochemical efficacy in vivo either by measuring their ability to suppress plasma and tissue estrogen levels or, alternatively, by measuring their ability to inhibit the conversion of tracer-labelled androstenedione into estrone. While contemporary methods for estrogen measurement (with the exception of estrone sulphate) lack the sensitivity to measure plasma estrogen levels during treatment with the most potent compounds, in vivo aromatase inhibition can be determined with a much better sensitivity. Thus, in a joint program conducted by the Royal Marsden Hospital, London and our team in Bergen, we were able to reveal profound differences between first- and second-generation aromatase inhibitors, causing 50-90% aromatase inhibition, and the three third-generation compounds, causing >98% inhibition of total body aromatization.

Androstenedione↗
PubMed2005

Effects of anastrozole on the intratumoral gene expression in locally advanced breast cancer.

Intratumoral levels of E1 (oestrone), E1S (oestrone sulphate) and E2 (oestradiol) are significantly reduced by treatment with the aromatase inhibitor anastrozole regardless of treatment response. The purpose of the present pilot study was to look for additional markers of biochemical response to aromatase inhibitors on mRNA expression level. Whole genome expression was studied using microarray analysis of breast cancer tissue from 12 patients with locally advanced tumors, both before and following 15 weeks of treatment with the aromatase inhibitor anastrozole (Arimidex). Intratumoral mRNA levels for a subset of genes coding for steroid metabolizing enzymes, hormone receptors and some growth mediators involved in cell cycle control were analysed by quantitative RT-PCR. There was a correlation between the two methods for some but not all genes. The mRNA expression levels of the different genes were correlated to each other and to the intratumoral levels of E1, E2 and E1S, before and after the treatment. Notably, a correlation of the E1/E2 metabolic ratio to the mRNA levels of CYP19A1 was observed before treatment (r=0.745, p<0.005). Whole genome expression analysis of these 12 breast cancer patients revealed similar tumor classification to previously published larger studies. Tumors with no or low expression of ESR1 (oestrogen receptor) clustered together and were characterized by a strong basal-like signature highly expressing keratins 5/17, cadherin 3, frizzled and apolipoprotein D, among others. The luminal epithelial tumor cluster, on the other hand, highly expressed ESR1, GATA binding protein 3 and N-acetyl transferase. An evident ERBB2 cluster was observed due to the marked over-expression of the ERBB2 gene and GRB7 and PPARBP in this patient material). Using significance analysis of microarrays (SAM), we identified 298 genes significantly differently expressed between the partial response and progressive disease groups.

Anastrozole↗
PubMed2005

Treatment with high-dose estrogen (diethylstilbestrol) significantly decreases plasma estrogen and androgen levels but does not influence in vivo aromatization in postmenopausal breast cancer patients.

While growth factors and hormones are known to influence aromatase expression in experimental systems, little is know about potential factors influencing peripheral aromatization in postmenopausal women. The fact that peripheral aromatase activity is higher in old compared to young women and the finding of relatively high tissue estradiol (E2) concentrations after the menopause suggests peripheral aromatization could be influenced by estrogen concentration. To test this hypothesis, we determined plasma hormone levels (n=9) and in vivo aromatization (n=3) in postmenopausal women suffering from advanced breast cancer before and during treatment (4 weeks) with diethylstilbestrol (DES) 5mg three times daily. Plasma levels of cortisol (C), corticosteroid-binding globulin (CBG), and sex hormone binding globulin (SHBG) were significantly increased in all patients (P<0.05 for all). While we found no change in total body aromatization and plasma estrone (E(1)) levels, estradiol (E(2)) and estrone sulfate (E(1)S) were suppressed by a mean of 48.8 and 68.2%, respectively (P=0.043 and 0.008). Surprisingly, plasma levels of androstenedione (A), testosterone (T), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) were also suppressed by a mean in the range of 32.1 to 52.6% (P<0.05 for all androgens). In contrast, no change in plasma progesterone or 17alpha-hydroxyprogesterone was found. Thus, one possible explanation to our findings could be that DES administered in high doses reduces 17,20-lyase activity in the adrenal gland.

Aged↗
PubMed2005

Genomics in breast cancer-therapeutic implications.

The introduction of DNA microarray techniques has had dramatic implications on cancer research, allowing researchers to analyze expression of multiple genes in concert and relate the findings to clinical parameters. The main discoveries in breast cancer, as well as in other malignancies, have so far been with respect to two key issues. First, individual tumors arising from the same organ may be grouped into distinct classes based on their gene expression profiles, independent of stage and grade. Second, the biologic relevance of such classification is corroborated by significant prognostic impact. We review how the use of microarray technologies can provide unique possibilities to explore the mechanisms of tumor behavior in vivo that will allow evaluation of prognosis and, potentially, drug resistance. However, in spite of recent advances, we are not yet at a stage where the use of these techniques should be implemented for routine clinical use, whether to define prognostic factors or to predict sensitivity to therapy.

Antineoplastic Agents↗
PubMed2005

Widespread dispersion of adeno-associated virus serotype 1 and adeno-associated virus serotype 6 vectors in the rat central nervous system and in human glioblastoma multiforme xenografts.

The transduction patterns of recombinant adeno-associated virus serotype 1 (AAV1) and serotype 6 (AAV6) vectors were assessed in human glioblastoma multiforme (GBM) cell lines, in human GBM biopsy spheroids, and in tumor xenografts growing in nude rat brains. All the cell lines tested (A172, D37, GaMg, HF66, and U373Mg) were found to be permissive to both AAV1 and AAV6 vectors, and thus displayed a transduction pattern similar to AAV2 vectors. For every cell line tested, the transduction efficiency displayed by AAV2 vectors was better than by isogenic and isopromoter AAV1 vectors. Transduction efficiency was dependent on the viral particle number used, suggesting that the receptors for these vectors are widely distributed in GBM tissues. Interestingly, AAV1, AAV2, and AAV6 vectors were able to infect and transduce the same cells when added simultaneously to monolayer cultures. Infection of human GBM biopsy spheroids with AAV1 and AAV6 vectors resulted in transgene expression both at the surface layers and in the core of the spheroids. Following injection of AAV1 and AAV6 vectors into human GBM biopsy xenografts growing in nude rat brains, reporter gene expression was seen both in the periphery as well as in the central regions of the tumors. When injected into the normal rat brain, both AAV1 and AAV6 vectors were found to transduce several central nervous system (CNS) regions. The presented results suggest a potential therapeutic role for AAV1 and AAV6 vectors in gene therapy for GBM and also for other CNS malignancies.

Animals↗
PubMed2005

Genomics-based prognosis and therapeutic prediction in breast cancer.

Breast cancer is a heterogeneous disease. DNA microarray technology is being applied to breast cancer to identify new prognostic biomarkers, to predict response to therapy, and to discover targets for the development of novel therapies. New diagnostic assays based on global gene expression are being introduced into clinical practice or tested in large-scale clinical trials. This review focuses on translational studies using microarray analyses and discusses best practice features and pitfalls. We note that factors that predict metastatic disease are not necessarily the same factors that predict therapeutic response. We believe that the characterization and discernment of different systems among breast cancers is crucial for understanding drug sensitivity and resistance mechanisms and for guiding therapy.

Antineoplastic Agents↗
PubMed2005

Prognostic and predictive value of changes in tumour cell proliferation in locally advanced breast cancer primarily treated with doxorubicin.

We previously reported that high tumour cell proliferation evaluated by Ki-67 expression, high mitotic frequency and high histological grade were associated with resistance to primary doxorubicin monotherapy in locally advanced breast cancer harbouring wild-type (wt) TP53. The aim of our present study was to evaluate the predictive and prognostic impact of proliferation parameters assessed in tumour tissue obtained after chemotherapy, and alterations induced in tumour cell proliferation. While we found a significant reduction in Ki-67 expression and mitotic frequency in tumours with wtTP53 (p=0.001 and p=0.008, respectively), no significant change was recorded in tumours expressing mutant TP53. For histological grade there was no significant change in either group. There was a direct correlation between pre- and post-treatment values for Ki-67 and mitotic frequency in tumours harbouring wtTP53 (p=0.0001 for both), but no correlation in tumours harbouring mutated TP53. High post-treatment Ki-67 expression and mitotic frequency were found to predict doxorubicin resistance only in patients with wtTP53 (p=0.04 and p=0.03, respectively). The prognostic importance of proliferation markers and histological grade was found to be similar whether they were determined in the pre- or post-treatment samples (Ki-67; pre: p=0.02; post: p=0.03; mitotic frequency; p=0.002 and p=0.01, respectively; histological grade; p=0.0001 and p=0.002, respectively). While the reduction in mitotic frequency was associated with improved survival (p=0.03), no significant associations between changes in other parameters and outcome were recorded.

Antibiotics, Antineoplastic↗