Peter Peschke
Research interests
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InterestsCancer Biology, Radiotherapy, Cancer Animal Models, Cancer Biomarkers, Cancer Cells
Publications
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6.75Impact points
LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP associated proinflammatory and proangiogenic signals.
Clinical cancer research : an official journal of the American Association for Cancer Research. 04/2012;
PURPOSE: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-beta signalling is considered to play an important role. EXPERIMENTAL DESIGN: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and ad... [more] PURPOSE: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-beta signalling is considered to play an important role. EXPERIMENTAL DESIGN: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small molecule TGF-beta-receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Non-invasive lung imaging including Volume Computed Tomography (VCT) and Magnetic Resonance Imaging (MRI) was performed 6, 16 and 20 weeks after irradiation and was correlated to histological findings. Expression profiling analysis and protein analysis was performed in human primary fibroblasts. RESULTS: Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced lifespan. VCT, MRI and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically we found that LY2109761 reduced pSMAD2 and pSMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and non-canonical TGF-beta signaling and downstream signaling of bone morphogenetic proteins (BMPs). LY2109761 also suppressed radiation-induced inflammatory (e.g. IL6, IL7R, IL8) and proangiogenic genes (e.g. ID1) indicating that LY2109761 achieves its antifibrotic effect by supressing radiation-induced proinflammatory, proangiogenic and profibrotic signals. CONCLUSION: Small molecule inhibitors of the TGF-beta-receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis.
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7.54Impact points
Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma.
Cancer research. 12/2011; 71(23):7155-67.
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhi... [more] Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFβR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFβR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma.
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Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-β receptor I kinase inhibitor LY2109761.
Neoplasia (New York, N.Y.). 06/2011; 13(6):537-49.
Here we investigate the effects of the novel transforming growth factor-β receptor I (TGF-βRI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter... [more] Here we investigate the effects of the novel transforming growth factor-β receptor I (TGF-βRI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated MGMT promoter), and endothelial cells (HUVECs) were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67) and the microvessel density (CD31 count), the relative pericyte coverage (α-SMA/CD31 ratio) increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-βRI kinase inhibitor to the present clinical standard (radiation plus TMZ) has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status.
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5.98Impact points
HPMA-based polymer therapeutics improve the efficacy of surgery, of radiotherapy and of chemotherapy combinations.
Nanomedicine (London, England). 12/2010; 5(10):1501-23.
To assist intravenously administered anticancer agents in achieving proper circulation times and tumor concentrations, and to thereby improve the balance between their efficacy and their toxicity, a large number of drug delivery systems have been designed and evaluated over the years. Clinically rel... [more] To assist intravenously administered anticancer agents in achieving proper circulation times and tumor concentrations, and to thereby improve the balance between their efficacy and their toxicity, a large number of drug delivery systems have been designed and evaluated over the years. Clinically relevant examples of such nanometer-sized carrier materials are liposomes, polymers, micelles and antibodies. In the vast majority of cases, however, and especially in patients, nanomedicine formulations are only able to attenuate the toxicity of the conjugated or entrapped chemotherapeutic drug, and they generally fail to improve the efficacy of the intervention. To overcome this shortcoming, and to broaden the clinical applicability of tumor-targeted nanomedicines, in the past 5 years we have developed several concepts for using N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer therapeutics to enhance the efficacy of combined modality anticancer therapy. Regarding surgery, HPMA copolymers were shown to be able to improve the retention of intratumorally administered chemotherapeutic agents at the pathological site, and to thereby increase their therapeutic index. Regarding radiotherapy, a synergistic interaction was observed, with radiotherapy improving the tumor accumulation of the copolymers, and with copolymers improving both the efficacy and the tolerability of radiochemotherapy. Futhermore, regarding chemotherapy combinations, we have for the first time provided in vivo evidence showing that passively tumor-targeted polymeric drug carriers can be used to deliver two different drugs to tumors simultaneously. Based on these findings, and on the fact that the concepts developed are considered to be broadly applicable, we conclude that nanomedicine formulations are highly suitable systems for improving the efficacy of combined modality anticancer therapy.
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2.27Impact points
Computer simulation of tumour control probabilities after irradiation for varying intrinsic radio-sensitivity using a single cell based model.
Acta oncologica (Stockholm, Sweden). 11/2010; 49(8):1354-62.
Currently, optimisation of the dose distribution and clinical acceptance are almost entirely based on the physical dose distribution and tumour control probability modelling is far from being routinely used as objective in treatment planning. For future individualised radiotherapeutic strategies, a ... [more] Currently, optimisation of the dose distribution and clinical acceptance are almost entirely based on the physical dose distribution and tumour control probability modelling is far from being routinely used as objective in treatment planning. For future individualised radiotherapeutic strategies, a reliable patient specific simulation model, taking into account customised tumour features, is needed to predict and improve treatment outcome. To approach these demands, a single cell and Monte-Carlo based model was developed, which enables three-dimensional tumour growth and radiation response simulation. Tumour cells were characterised by cell-associated features such as age, intrinsic radio-sensitivity, proliferation ability, and oxygenation status, while capillary cells were considered as sources of a radial-dependent oxygen profile. Response to radiation was simulated by the linear-quadratic model, taking into account the lower radio-sensitivity of poorly oxygenated tumour cells. The present study shows the influence of the model components and demonstrates the impact of the intra- and inter-tumoural radio-sensitivity heterogeneity on the treatment response. The simulation model adequately delineates the importance of the above described selected parameters on tumour control probability, providing an insight into the interplay of different physical and biological parameters, and its relevance for an individual tumour response.
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4.59Impact points
Relative biological effectiveness of carbon ions for local tumor control of a radioresistant prostate carcinoma in the rat.
International journal of radiation oncology, biology, physics. 10/2010; 79(1):239-46.
To study the relative biological effectiveness (RBE) of carbon ion beams relative to X-rays for local tumor control in a syngeneic rat prostate tumor (Dunning subline R3327-AT1). A total of 198 animals with tumors in the distal thigh were treated with increasing single and split doses of either (12)... [more] To study the relative biological effectiveness (RBE) of carbon ion beams relative to X-rays for local tumor control in a syngeneic rat prostate tumor (Dunning subline R3327-AT1). A total of 198 animals with tumors in the distal thigh were treated with increasing single and split doses of either (12)C ions or photons using a 20-mm spread-out Bragg peak. Endpoints of the study were local control (no tumor recurrence within 300 days) and volumetric changes after irradiation. The resulting values for D(50) (dose at 50% tumor control probability) were used to determine RBE values. The D(50) values for single doses were 32.9 ± 0.9 Gy for (12)C ions and 75.7 ± 1.6 Gy for photons. The respective values for split doses were 38.0 ± 2.3 Gy and 90.6 ± 2.3 Gy. The corresponding RBE values were 2.30 ± 0.08 for single and 2.38 ± 0.16 for split doses. The most prominent side effects were dry and moist desquamation of the skin, which disappeared within weeks. The study confirmed the effectiveness of carbon ion therapy for severely radioresistant tumors. For 1- and 2-fraction photon and (12)C ion radiation, we have established individual D(50) values for local tumor control as well as related RBE values.
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Multimodality imaging of hypoxia in preclinical settings.
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of Radiopharmaceutical Chemistry and Biology. 06/2010; 54(3):259-80.
Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypo... [more] Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypoxia. This review will examine diverse approaches focusing on the preclinical setting, particularly, in rodents. The strategies are inevitably a compromise in terms of sensitivity, precision, temporal and spatial resolution, as well as cost, feasibility, ease and robustness of implementation. We will review capabilities of multiple modalities and examine what makes them particularly suitable for investigating specific aspects of tumor pathophysiology. Current approaches range from nuclear imaging to magnetic resonance and optical, with varying degrees of invasiveness and ability to examine spatial heterogeneity, as well as dynamic response to interventions. Ideally, measurements would be non-invasive, exploiting endogenous reporters to reveal quantitatively local oxygen tension dynamics. A primary focus of this review is magnetic resonance imaging (MRI) based techniques, such as ¹⁹F MRI oximetry, which reveals not only hypoxia in vivo, but more significantly, spatial distribution of pO₂ quantitatively, with a precision relevant to radiobiology. It should be noted that preclinical methods may have very different criteria for acceptance, as compared with potential investigations for prognostic radiology or predictive biomarkers suitable for use in patients.
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Molecular ultrasound imaging of early vascular response in prostate tumors irradiated with carbon ions.
Neoplasia (New York, N.Y.). 10/2009; 11(9):856-63.
Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. Fo... [more] Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1) and of alpha(v)beta(3)-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy) was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of alpha(v)beta(3)-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of alpha(v)beta(3)-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and alpha(v)beta(3)-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.
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4.59Impact points
Comparison of biological effectiveness of carbon-ion beams in Japan and Germany.
International journal of radiation oncology, biology, physics. 05/2009; 73(5):1545-51.
PURPOSE: To compare the biological effectiveness of 290 MeV/amu carbon-ion beams in Chiba, Japan and in Darmstadt, Germany, given that different methods for beam delivery are used for each. METHODS AND MATERIALS: Murine small intestine and human salivary gland tumor (HSG) cells exponentially growing... [more] PURPOSE: To compare the biological effectiveness of 290 MeV/amu carbon-ion beams in Chiba, Japan and in Darmstadt, Germany, given that different methods for beam delivery are used for each. METHODS AND MATERIALS: Murine small intestine and human salivary gland tumor (HSG) cells exponentially growing in vitro were irradiated with 6-cm width of spread-out Bragg peaks (SOBPs) adjusted to achieve nearly identical beam depth-dose profiles at the Heavy-Ion Medical Accelerator in Chiba, and the SchwerIonen Synchrotron in Darmstadt. Cell kill efficiencies of carbon ions were measured by colony formation for HSG cells and jejunum crypts survival in mice. Cobalt-60 gamma rays were used as the reference radiation. Isoeffective doses at given survivals were used for relative biological effectiveness (RBE) calculations and interinstitutional comparisons. RESULTS: Isoeffective D(10) doses (mean +/- standard deviation) of HSG cells ranged from 2.37 +/- 0.14 Gy to 3.47 +/- 0.19 Gy for Chiba and from 2.31 +/- 0.11 Gy to 3.66 +/- 0.17 Gy for Darmstadt. Isoeffective D(10) doses of gut crypts after single doses ranged from 8.25 +/- 0.17 Gy to 10.32 +/- 0.14 Gy for Chiba and from 8.27 +/- 0.10 Gy to 10.27 +/- 0.27 Gy for Darmstadt, whereas isoeffective D(30) doses after three fractionated doses were 9.89 +/- 0.17 Gy through 13.70 +/- 0.54 Gy and 10.14 +/- 0.20 Gy through 13.30 +/- 0.41 Gy for Chiba and Darmstadt, respectively. Overall difference of RBE between the two facilities was 0-5% or 3-7% for gut crypt survival or HSG cell kill, respectively. CONCLUSION: The carbon-ion beams at the National Institute of Radiological Sciences in Chiba, Japan and the Gesellschaft für Schwerionenforschung in Darmstadt, Germany are biologically identical after single and daily fractionated irradiation.
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7.37Impact points
Simultaneous delivery of doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers.
Biomaterials. 04/2009;
Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer therapeutics. To demonstrate that polymers, as liposomes, can be used for simultaneously delivering multiple chemother... [more] Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer therapeutics. To demonstrate that polymers, as liposomes, can be used for simultaneously delivering multiple chemotherapeutic agents to tumors in vivo, we have synthesized and evaluated an HPMA-based polymer-drug conjugate carrying 6.4wt% of gemcitabine, 5.7wt% of doxorubicin and 1.0mol% of tyrosinamide (to allow for radiolabeling). The resulting construct, i.e. poly(HPMA-co-MA-GFLG-gemcitabine-co-MA-GFLG-doxorubicin-co-MA-TyrNH(2)), was termed P-Gem-Dox, and was shown to effectively kill cancer cells in vitro, to circulate for prolonged period of time, to localize to tumors relatively selectively, and to inhibit tumor growth. As compared to control regimens, P-Gem-Dox increased the efficacy of the combination of gemcitabine and doxorubicin without increasing its toxicity, and it more strongly inhibited angiogenesis and induced apoptosis. These findings demonstrate that passively tumor-targeted polymeric drug carriers can be used for delivering two different chemotherapeutic agents to tumors simultaneously, and they thereby set the stage for more elaborate analyses on the potential of polymer-based multi-drug targeting.
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4.59Impact points
What is the clinically relevant relative biologic effectiveness? A warning for fractionated treatments with high linear energy transfer radiation: in regard to Daşu and Toma-DAşu. (Int J Radiat Oncol Biol Phys 2008;70:867-874).
International journal of radiation oncology, biology, physics. 05/2008; 70(5):1614; author reply 1614-5.
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2.02Impact points
Gonadotrophin releasing hormone-based vaccine, an effective candidate for prostate cancer and other hormone-sensitive neoplasms.
Advances in experimental medicine and biology. 01/2008; 617:581-7.
Prostate growth, development, functions, and neoplastic transformation is androgen dependent. Estrogens have similar effects in the ovary and breast. Previous studies using gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate... [more] Prostate growth, development, functions, and neoplastic transformation is androgen dependent. Estrogens have similar effects in the ovary and breast. Previous studies using gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate (PC) and breast cancer (BC). We have synthesized a peptide mutated at position 6 and attached to the 830-844 tetanic toxoid (TT) helper T cell sequence in the same synthesis process. After repeated pig immunizations, we have demonstrated a vaccine that significantly decreased testes size (p < 0.001), prostate (p < 0.01), seminal vesicles (p < 0.01), and testosterone (T) castration [0.05 nM ml(-1) (p < 0. 01)]. Similar results were obtained in adult male and female healthy dogs and Macaca fascicularis models. These data indicate that this GnRHm1-TT vaccine is safe and able to induce significant tumor growth inhibition in the Dunning R3327-H rat androgen responsive prostate tumor model. In these rats, the immunization induced high anti-GnRH titers concomitant with T castration reduction (p < 0.01) in 90% of the animals tested. In addition, 70% of the responders exhibited tumor growth inhibition (p = 0.02) and a survival rate approximately three times longer that those of untreated rats. These data indicate that GnRHm1-TT vaccine may be a potential candidate in the treatment of PC, BC, and other hormone-dependent cancers.
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3.62Impact points
Immunotherapy of prostate cancer in a murine model using a novel GnRH based vaccine candidate.
Vaccine. 01/2008; 25(50):8460-8.
Previous studies with gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate cancer. To this end, we have generated a completely synthetic peptide modified at position 6 and attached to the 830-844 tetanic toxoid (TT) helper T ... [more] Previous studies with gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate cancer. To this end, we have generated a completely synthetic peptide modified at position 6 and attached to the 830-844 tetanic toxoid (TT) helper T cell sequence. Through this work we have demonstrated that the GnRHm1-TT molecule was highly immunogenic when it is formulated as an oil-based emulsion adjuvated with Montanide ISA 51. That results correlated directly with testosterone reduction and tumor growth inhibition of the Dunning R3327-H androgen responsive prostate tumor model in rats. GnRHm1-TT, proved to be safe and useful for future clinical trials.
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4.85Impact points
Retrospective motion gating in small animal CT of mice and rats.
Investigative radiology. 11/2007; 42(10):704-14.
OBJECTIVES: Implementation and evaluation of retrospective respiratory and cardiac gating of mice and rats using a flat-panel volume-CT prototype (fpVCT). MATERIALS AND METHODS: Respiratory and cardiac gating was implemented by equipping a fpVCT with a small animal monitoring unit. ECG and breathing... [more] OBJECTIVES: Implementation and evaluation of retrospective respiratory and cardiac gating of mice and rats using a flat-panel volume-CT prototype (fpVCT). MATERIALS AND METHODS: Respiratory and cardiac gating was implemented by equipping a fpVCT with a small animal monitoring unit. ECG and breathing excursions were recorded and 2 binary gating signals derived. Mice and rats were scanned continuously over 80 seconds after administration of blood-pool contrast media. Projections were chosen to reconstruct volumes that fall within defined phases of the cardiac/respiratory cycle. RESULTS: Multireader analysis indicated that in gated still images motion artifacts were strongly reduced and diaphragm, tracheobronchial tract, heart, and vessels sharply delineated. From 4D series, functional data such as respiratory tidal volume and cardiac ejection fraction were calculated and matched well with values known from literature. DISCUSSION: Implementation of retrospective gating in fpVCT improves image quality and opens new perspectives for functional cardiac and lung imaging in small animals.
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2.78Impact points
Single-cell-based computer simulation of the oxygen-dependent tumour response to irradiation.
Physics in medicine and biology. 09/2007; 52(16):4775-89.
Optimization of treatment plans in radiotherapy requires the knowledge of tumour control probability (TCP) and normal tissue complication probability (NTCP). Mathematical models may help to obtain quantitative estimates of TCP and NTCP. A single-cell-based computer simulation model is presented, whi... [more] Optimization of treatment plans in radiotherapy requires the knowledge of tumour control probability (TCP) and normal tissue complication probability (NTCP). Mathematical models may help to obtain quantitative estimates of TCP and NTCP. A single-cell-based computer simulation model is presented, which simulates tumour growth and radiation response on the basis of the response of the constituting cells. The model contains oxic, hypoxic and necrotic tumour cells as well as capillary cells which are considered as sources of a radial oxygen profile. Survival of tumour cells is calculated by the linear quadratic model including the modified response due to the local oxygen concentration. The model additionally includes cell proliferation, hypoxia-induced angiogenesis, apoptosis and resorption of inactivated tumour cells. By selecting different degrees of angiogenesis, the model allows the simulation of oxic as well as hypoxic tumours having distinctly different oxygen distributions. The simulation model showed that poorly oxygenated tumours exhibit an increased radiation tolerance. Inter-tumoural variation of radiosensitivity flattens the dose response curve. This effect is enhanced by proliferation between fractions. Intra-tumoural radiosensitivity variation does not play a significant role. The model may contribute to the mechanistic understanding of the influence of biological tumour parameters on TCP. It can in principle be validated in radiation experiments with experimental tumours.
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9.43Impact points
Transcriptional network governing the angiogenic switch in human pancreatic cancer.
Proceedings of the National Academy of Sciences of the United States of America. 08/2007; 104(31):12890-5.
A shift of the angiogenic balance to the proangiogenic state, termed the "angiogenic switch," is a hallmark of cancer progression. Here we devise a strategy for identifying genetic participants of the angiogenic switch based on inverse regulation of genes in human endothelial cells in resp... [more] A shift of the angiogenic balance to the proangiogenic state, termed the "angiogenic switch," is a hallmark of cancer progression. Here we devise a strategy for identifying genetic participants of the angiogenic switch based on inverse regulation of genes in human endothelial cells in response to key endogenous pro- and antiangiogenic proteins. This approach reveals a global network pattern for vascular homeostasis connecting known angiogenesis-related genes with previously unknown signaling components. We also demonstrate that the angiogenic switch is governed by simultaneous regulations of multiple genes organized as transcriptional circuitries. In pancreatic cancer patients, we validate the transcriptome-derived switch of the identified "angiogenic network:" The angiogenic state in chronic pancreatitis specimens is intermediate between the normal (angiogenesis off) and neoplastic (angiogenesis on) condition, suggesting that aberrant proangiogenic environment contributes to the increased cancer risk in patients with chronic pancreatitis. In knockout experiments in mice, we show that the targeted removal of a hub node (peroxisome proliferative-activated receptor delta) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor delta expression levels are correlated with advanced pathological tumor stage, increased risk for tumor recurrence, and distant metastasis. Our results therefore also may contribute to the rational design of antiangiogenic cancer agents; whereas "narrow" targeted cancer drugs may fail to shift the robust angiogenic regulatory network toward antiangiogenesis, the network may be more vulnerable to multiple or broad-spectrum inhibitors or to the targeted removal of the identified angiogenic "hub" nodes.
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5.95Impact points
Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems.
Journal of controlled release : official journal of the Controlled Release Society. 03/2007; 117(3):333-41.
Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer therapeutics. In an attempt to improve the tumor accumulation of HPMA copolymer-based drug delivery systems, their in ... [more] Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer therapeutics. In an attempt to improve the tumor accumulation of HPMA copolymer-based drug delivery systems, their in vivo application was combined with radiotherapy and hyperthermia. As the effects of radiotherapy and hyperthermia were considered to depend significantly on the tumor model used, we first analyzed the accumulation of two differently sized HPMA copolymers in three different types of tumors, based on the syngeneic Dunning rat prostate carcinoma model. Subsequently, in these three models, the effects of different doses of radiotherapy and hyperthermia on the tumor accumulation of 31 kDa poly(HPMA), 65 kDa poly(HPMA) and 28 kDa poly(HPMA)-GFLG-doxorubicin were evaluated. It was found that the polymeric drug delivery systems accumulated effectively in all three tumor models. In addition, as opposed to hyperthermia, radiotherapy was found to improve the concentrations of the copolymers independent of the tumor model used. Based on these findings, we conclude that radiotherapy is an effective means for increasing the tumor accumulation of (polymeric) drug delivery systems, and we propose that the combination of carrier-based chemotherapy with radiotherapy holds significant potential for improving the treatment of advanced solid malignancies.
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Impact of stroma on the growth, microcirculation, and metabolism of experimental prostate tumors.
Neoplasia (New York, N.Y.). 02/2007; 9(1):57-67.
In prostate cancers (PCa), the formation of malignant stroma may substantially influence tumor phenotype and aggressiveness. Thus, the impact of the orthotopic and subcutaneous implantations of hormone-sensitive (H), hormone-insensitive (HI), and anaplastic (AT1) Dunning PCa in rats on growth, micro... [more] In prostate cancers (PCa), the formation of malignant stroma may substantially influence tumor phenotype and aggressiveness. Thus, the impact of the orthotopic and subcutaneous implantations of hormone-sensitive (H), hormone-insensitive (HI), and anaplastic (AT1) Dunning PCa in rats on growth, microcirculation, and metabolism was investigated. For this purpose, dynamic contrast-enhanced magnetic resonance imaging and (1)H magnetic resonance spectroscopy ([(1)H]MRS) were applied in combination with histology. Consistent observations revealed that orthotopic H tumors grew significantly slower compared to subcutaneous ones, whereas the growth of HI and AT1 tumors was comparable at both locations. Histologic analysis indicated that glandular differentiation and a close interaction of tumor cells and smooth muscle cells (SMC) were associated with slow tumor growth. Furthermore, there was a significantly lower SMC density in subcutaneous H tumors than in orthotopic H tumors. Perfusion was observed to be significantly lower in orthotopic H tumors than in subcutaneous H tumors. Regional blood volume and permeability-surface area product showed no significant differences between tumor models and their implantation sites. Differences in growth between subcutaneous and orthotopic H tumors can be attributed to tumor-stroma interaction and perfusion. Here, SMC, may stabilize glandular structures and contribute to the maintenance of differentiated phenotype.
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4.16Impact points
Role of PP2Calpha in cell growth, in radio- and chemosensitivity, and in tumorigenicity.
Molecular cancer. 02/2007; 6:65.
BACKGROUND: PP2Calpha is the representative member of the type 2C family of protein phosphatases, and it has recently been implicated in the regulation of p53-, TGFbeta-, cyclin-dependent kinase- and apoptosis-signaling. To investigate the role of PP2Calpha in cell growth and in radio- and chemosens... [more] BACKGROUND: PP2Calpha is the representative member of the type 2C family of protein phosphatases, and it has recently been implicated in the regulation of p53-, TGFbeta-, cyclin-dependent kinase- and apoptosis-signaling. To investigate the role of PP2Calpha in cell growth and in radio- and chemosensitivity, wild type and PP2Calpha siRNA-expressing MCF7 cells were subjected to several different viability and cell cycle analyses, both under basal conditions and upon treatment with radio- and chemotherapy. By comparing the growth of tumors established from both types of cells, we also evaluated the involvement of PP2Calpha in tumorigenesis. RESULTS: It was found that knockdown of PP2Calpha did not affect the proliferation, the clonogenic survival and the membrane integrity of MCF7 cells. In addition, it did not alter their radio- and chemosensitivity. For PP2Calpha siRNA-expressing MCF7 cells, the number of cells in the G0/G1 phase of the cell cycle was reduced, the induction of the G1 block was attenuated, the number of cells in G2/M was increased, and the induction of the G2 block was enhanced. The tumorigenic potential of PP2Calpha siRNA-expressing MCF7 cells was found to be higher than that of wild type MCF7 cells, and the in vivo proliferation of these cells was found to be increased. CONCLUSION: Based on these findings, we conclude that PP2Calpha is not involved in controlling cell growth and radio- and chemosensitivity in vitro. It does, however, play a role in the regulation of the cell cycle, in the induction of cell cycle checkpoints and in tumorigenesis. The latter notion implies that PP2Calpha may possess tumor-suppressing properties, and it thereby sets the stage for more elaborate analyses on its involvement in the development and progression of cancer.
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Role of PP2Cα in cell growth, in radio- and chemosensitivity, and in tumorigenicity
Molecular Cancer. 01/2007;
Abstract Background PP2Cα is the representative member of the type 2C family of protein phosphatases, and it has recently been implicated in the regulation of p53-, TGFβ-, cyclin-dependent kinase- and apoptosis-signaling. To investigate the role of PP2Cα in cell growth and in radio- and chemosensi... [more] Abstract Background PP2Cα is the representative member of the type 2C family of protein phosphatases, and it has recently been implicated in the regulation of p53-, TGFβ-, cyclin-dependent kinase- and apoptosis-signaling. To investigate the role of PP2Cα in cell growth and in radio- and chemosensitivity, wild type and PP2Cα siRNA-expressing MCF7 cells were subjected to several different viability and cell cycle analyses, both under basal conditions and upon treatment with radio- and chemotherapy. By comparing the growth of tumors established from both types of cells, we also evaluated the involvement of PP2Cα in tumorigenesis. Results It was found that knockdown of PP2Cα did not affect the proliferation, the clonogenic survival and the membrane integrity of MCF7 cells. In addition, it did not alter their radio- and chemosensitivity. For PP2Cα siRNA-expressing MCF7 cells, the number of cells in the G0/G1 phase of the cell cycle was reduced, the induction of the G1 block was attenuated, the number of cells in G2/M was increased, and the induction of the G2 block was enhanced. The tumorigenic potential of PP2Cα siRNA-expressing MCF7 cells was found to be higher than that of wild type MCF7 cells, and the in vivo proliferation of these cells was found to be increased. Conclusion Based on these findings, we conclude that PP2Cα is not involved in controlling cell growth and radio- and chemosensitivity in vitro. It does, however, play a role in the regulation of the cell cycle, in the induction of cell cycle checkpoints and in tumorigenesis. The latter notion implies that PP2Cα may possess tumor-suppressing properties, and it thereby sets the stage for more elaborate analyses on its involvement in the development and progression of cancer.
Following (14)
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Osvaldo Reyes
Center for Genetic Engineering and Biotechnology -
Moritz Palmowski
Rheinisch-Westfälische Technische Hochschule Aachen -
Thomas Haberer
Universität Heidelberg -
Ute Wirkner
Deutsches Krebsforschungszentrum -
Wim E Hennink
Universiteit Utrecht
