No abstract

Purpose To examine the potential use of BOLD (Blood Oxygenation Level Dependent) and TOLD (Tissue Oxygenation Level Dependent) contrast MRI to assess tumor oxygenation and predict radiation response. Methods BOLD and TOLD MRI were performed on Dunning R3327-AT1 rat prostate tumors during hyperoxic gas breathing challenge at 4.7 T. Animals were divided into two groups. In Group 1 (n=9), subsequent 19F MRI based on spin lattice relaxation of hexafluorobenzene reporter molecule provided quantitative oximetry for comparison. For Group 2 rats (n=13) growth delay following a single dose of 30 Gy was compared with pre-irradiation BOLD and TOLD assessments. Results Oxygen (100%O2) and carbogen (CB; 95%O2/5%CO2) challenge elicited similar BOLD, TOLD and pO2 responses. Strong correlations were observed between BOLD or R2* response and quantitative 19F pO2 measurements. TOLD response showed a general trend with weaker correlation. Irradiation caused a significant tumor growth delay and tumors with larger changes in TOLD and R1 values upon oxygen breathing exhibited significantly increased tumor growth delay. Conclusion These results provide further insight into the relationships between oxygen sensitive (BOLD/TOLD) MRI and tumor pO2. Moreover, a larger increase in R1 response to hyperoxic gas challenge coincided with greater tumor growth delay following irradiation.

Carbon ion therapy is a promising evolving modality in radiotherapy to treat tumors that are radioresistant against photon treatments. As carbon ions are more effective in normal and tumor tissue, the relative biological effectiveness (RBE) has to be calculated by bio-mathematical models and has to be considered in the dose prescription. This review (i) introduces the concept of the RBE and its most important determinants, (ii) describes the physical and biological causes of the increased RBE for carbon ions, (iii) summarizes available RBE measurements in vitro and in vivo, and (iv) describes the concepts of the clinically applied RBE models (mixed beam model, local effect model, and microdosimetric-kinetic model), and (v) the way they are introduced into clinical application as well as (vi) their status of experimental and clinical validation, and finally (vii) summarizes the current status of the use of the RBE concept in carbon ion therapy and points out clinically relevant conclusions as well as open questions. The RBE concept has proven to be a valuable concept for dose prescription in carbon ion radiotherapy, however, different centers use different RBE models and therefore care has to be taken when transferring results from one center to another. Experimental studies significantly improve the understanding of the dependencies and limitations of RBE models in clinical application. For the future, further studies investigating quantitatively the differential effects between normal tissues and tumors are needed accompanied by clinical studies on effectiveness and toxicity.

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-b is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-b receptor (TGFbR) 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 TGFbR-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 TGFbR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma. Cancer Res; 71(23); 7155-67. Ó2011 AACR.

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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 angiogenesisrelated 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 ␦) of the angiogenic network markedly impairs angiogenesis and tumor growth. Further, in tumor patients, we show that peroxisome proliferative-activated receptor ␦ 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.angiogenesis ͉ cancer therapy ͉ homeostatic balance ͉ systems biology ͉ pancreatic carcinoma

Drug targeting systems are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-) therapeutics. Reasoning that (I) the temporal and spatial interaction between systemically applied chemotherapy and clinically relevant fractionated radiotherapy is suboptimal, and that (II) drug targeting systems are able to improve the temporal and spatial parameters of this interaction, we have here set out to evaluate the potential of 'carrier-based radiochemotherapy'. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were used as a model drug targeting system, doxorubicin and gemcitabine as model drugs, and the syngeneic and radio-and chemoresistant Dunning AT1 rat prostate carcinoma as a model tumour model. Using magnetic resonance imaging and g-scintigraphy, the polymeric drug carriers were first shown to circulate for prolonged periods of time, to localise to tumours both effectively and selectively, and to improve the tumour-directed delivery of low molecular weight agents. Subsequently, they were then shown to interact synergistically with radiotherapy, with radiotherapy increasing the tumour accumulation of the copolymers, and with the copolymers increasing the therapeutic index of radiochemotherapy (both for doxorubicin and for gemcitabine). Based on these findings, and on the fact that its principles are likely broadly applicable, we propose carrier-based radiochemotherapy as a novel concept for treating advanced solid malignancies.

It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G 1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 F 2.6 to 4.2 F 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/ chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy. (Cancer Res 2005; 65(9): 3643-55)