Krebswissenschaft und -therapie

Osteopontin (OPN) is a secreted phosphoprotein whic h plays a critical role in metastasis of colon, liver , and breast cancers. The canonical pathway for OPN signaling fo cuses on its binding interactions with integrin and CD44 cell surface receptors. However, the binding characteri stics of OPN to integrin and CD44 receptors has not been pre vi- ously examined. In this paper, using MDA-MB231 brea st cancer and SK-Hep-1 liver cancer cells, we determin e the relative binding characteristics of the OPN ligand to its integrin and CD44 cell surface receptors. The appar ent K D ’s for binding to CD44 was 56 μ M and 49 μ M and to integrin was 18 μ M and 17 μ M, in SK-Hep-1 and MDA- MB231, respectively. The CD44/Integrin ratio of OP N bound was 1.3 and 3.8 in SK-Hep-1 and MDA-MB231, respectively. Our results indicate that OPN binds t o it rec- ognized receptors with substantially different affi nities, receptor expression varies between cell types, and signifi- cant OPN cell surface interactions that are integri n- and CD44-independent. These uncharacterized interaction s may reveal important insights into OPN’s role in ca ncer metastasis.

To provide more clinically convenient image fusions for adaptive radiotherapy (ART), an automatic rigid and deformable image registration framework (AIRF) is developed for multimodal visualization of multiple chronological images and multiple radiotherapy (RT) plans. Our hybrid image registration framework, AIRF, uses a faster but less accurate rigid registration method to provide an initial registration, followed by a slower but more accurate deformable registration method to fine tune the final registration. A multi-resolution approach is also employed in the image registration process to further improve the registration accuracy, robustness and efficiency. Volume visualization is provided to guide the automatic image registration process because it can reduce the global positioning error that results from a partial 3D visual presentation in the three conventional orthogonal planar views (axial, sagittal, and coronal). The AIRF can automatically align multiple volumetric images of patients taken over an extended period of time and can merge multiple radiotherapy plans based on different planning computed tomography (CT) images. It offers illustrative 3D volumetric visualization, hybrid rigid and deformable image registration, and automatic transfer of RT dose distribution and RT structure models such as treatment targets and organs at risk (OARs) onto chronological images. The AIRF can automatically register multiple volumetric image datasets of patients taken over an extended period of time and can merge multiple RT plans based on different planning CT images for 4D or adaptive radiotherapy.

Traditional risk factors for breast cancer explain only a fraction of cases. Causes for trends in breast cancer incidence are not fully understood. Breast cancer incidence and mortality rates decrease with environmental conditions that promote Vitamin D synthesis in human skin including lower latitude and higher personal exposure to sunlight. Association of temporal variability in breast cancer incidence with changes in cloudiness, which decrease human Vitamin D synthesis is investigated. Association between temporal changes in breast cancer incidence and in the autumn cloudiness for preceding years is computed using data for the United States. There is a correlation of 0.96 (95%CI=0.92-1) between the time series of breast cancer incidence in the age group of 70-79 years and the average cloudiness in October during preceding 20 years. An empirical model for breast cancer incidence using autumn cloudiness in preceding years captures a rapid increase in breast cancer incidence in the 1980s and some of its yearto- year variability. Increased autumn cloudiness is associated with increased subsequent breast cancer incidence. Proposed mechanism includes blocking of solar ultraviolet radiation by thick clouds and decreasing the synthesis of Vitamin D in human skin. The findings suggest a new connection between climate variability and human health.

Skin toxicity is the most common adverse event associated with the use of EGFR inhibitors. Radiation dermatitis occurs to some degree in most of the patients who receive radiotherapy, either alone or in combination with EGFR inhibitors. The effects of both toxicities might be additive because the irradiated skin zone in squamous cell cancer of the head and neck (SCCHN) patients is the same area in which the EGFR inhibitor-related acne-like rash is more common. This article summarizes the principal issues discussed during a symposium that took place in Madrid in January 2009, in which the management of cutaneous toxicity and radiation dermatitis in patients with SCCHN was reviewed. Selection of the most appropriate control measures was discussed in an interactive debate with the audience using five case reports. It was concluded that early establishment of adequate preventive measures and proper management of both the EGFR inhibitor-related, acne-like rash and radiation dermatitis in SCCHN patients undergoing concomitant treatment will prevent treatment interruption, potentially allowing better locoregional control of the disease.

Summary: Illumina BeadArray platform (Illumina Inc.) is playing an increasing role in cancer research. MBCB, an R package designed for use on Illumina Bead-Array data, allows for microarray data to be pre-processed through various model-based statistical methods. These model-based background-correction methods have proven to be a significant improvement over the traditional methods provided by Illumina in their BeadStudio software. MBCB accepts the summarized bead-type data; the data can then be normalized and background-corrected in a statistically-efficient manner. When compared to the popular Robust multi-array (RMA) background correction approach and the default, Illuminaprovided background-correction method, MBCB has shown to lead to more precise determination of gene expression and better biological interpretation of Illumina BeadArray data. The software developed will facilitate molecular biomedical - especially cancer - research. Availability: This package will soon be available from Bioconductor. Instructions for use are included with the package.

The screening process for potential anticancer drugs involves expensive and time consuming preclinical and clinical trials (CT) before a drug is approved for clinical use (CU). At present, there is a “bottleneck” at the CT/CU transition because many drugs that showed promising results during preclinical research did not pass clinical trials. We speculated that the endpoint parameters (the inhibitory concentration 50 (IC50) or lethal concentration 100 (CL100)) commonly used in proliferation assays for short-term periods (24-72 h) are not useful to predict the antiproliferative effect in vivo, especially during clinical trials. We propose the use of a parameter, regrowth concentration 0 (RC0), which will define the concentration and time necessary to kill 100 % of the cells and prevent regrowth when drug is removed. The RC0 might introduce a new bottleneck at the preclinical stage, “preclinical bottleneck”, that will select for drugs with more chances to pass clinical trials and improve the success rate of anticancer screening programs. Our proposal is supported by experiments done with the DBTRG-05MG human glioma cell lines exposed to short and long-term incubation with three different DNA replication inhibitors (aphidicolin, hydroxyurea and etoposide) and retrospective analysis of clinical trials for these drugs.

The aim of the present study is to identify an effective and efficient expression system for purification of recombinant antiangiogenic protein tumstatin. The sequence encoding carboxy-terminal non-collagenous domain of ?3 chain Type IV collagen, a3(IV)NC1 (tumstatin) was isolated from human placental tissue and cloned in three different expression vectors pET22b, pcBFT and pAcHLTA to express it in bacteria, mammalian and Sf-9 insect cells respectively. Expression and purification profiles of tumstatin were evaluated by coomassie staining and immunoblotting, and the efficiency was determined based on the yields of soluble protein. Our results indicate that, baculovirus expression system was efficient for scalable yields of soluble protein that could be purified in its biologically active form. This baculovirus expressed tumstatin was used to evaluate its anti-angiogenic and anti-tumarogenic functions such as inhibition of endothelial cell proliferation, cell viability, migration, tube formation, cap dependent protein translation and the associated signaling mechanism including in-vivo tumor study. Our evaluated approaches using a modified baculovirus expression system shows high expression and high yield of biologically active tumstatin, as compared to two expression systems, indicating baculovirus expression system to be an ideal method for bulk production of soluble tumstatin that needed for pre-clinical and clinical trails.

Targeted internal radionuclide therapy (TRT) would be an effective alternative to current therapies for disseminated melanoma treatment. At our institution, a class of iodobenzamides has been developed as potent melanomaseeking agents. This review described the preclinical validations of a quinoxaline derivative molecule (ICF01012) as tracer for TRT application. It was selected for its high, specific and long-lasting uptake in tumour with rapid clearance from non-target organs providing suitable dosimetry parameters for TRT. Extended in vivo study of metabolic profiles confirmed durable tumoural concentration of the unchanged molecule form. Moreover melanin specificity of ICF01012 was determined by binding assay with synthetic melanin and in vivo by SIMS imaging. Then, we showed in vivo that [131I] ICF01012 treatment drastically inhibited growth of B16F0, B16Bl6 and M4Beu tumours whereas [131I] NaI or unlabelled ICF01012 treatment was without significant effect. Histological analysis showed that residual tumour cells exhibit a significant loss of aggressiveness after treatment. This anti-tumoural effect was associated with a lengthening of the treated-mice survival time and an inhibition of lung dissemination for B16Bl6 model. Results presented here support the concept of TRT using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment.