scholarly journals Targeted and Non-Targeted Mechanisms for Killing Hypoxic Tumour Cells—Are There New Avenues for Treatment?

2021 ◽  
Vol 22 (16) ◽  
pp. 8651
Author(s):  
Alyssa Gabrielle Apilan ◽  
Carmel Mothersill

Purpose: A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new “target”. Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. Conclusions: This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled “oxygenate, target, use, and digest”. In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.

2010 ◽  
Vol 49 (S 01) ◽  
pp. S53-S58 ◽  
Author(s):  
W. Dörr

SummaryThe curative effectivity of external or internal radiotherapy necessitates exposure of normal tissues with significant radiation doses, and hence must be associated with an accepted rate of side effects. These complications can not a priori be considered as an indication of a too aggressive therapy. Based on the time of first diagnosis, early (acute) and late (chronic) radiation sequelae in normal tissues can be distinguished. Early reactions per definition occur within 90 days after onset of the radiation exposure. They are based on impairment of cell production in turnover tissues, which in face of ongoing cell loss results in hypoplasia and eventually a complete loss of functional cells. The latent time is largely independent of dose and is defined by tissue biology (turnover time). Usually, complete healing of early reactions is observed. Late radiation effects can occur after symptom-free latent times of months to many years, with an inverse dependence of latency on dose. Late normal tissue changes are progressive and usually irreversible. They are based on a complex interaction of damage to various cell populations (organ parenchyma, connective tissue, capillaries), with a contribution from macrophages. Late effects are sensitive for a reduction in dose rate (recovery effects).A number of biologically based strategies for protection of normal tissues or for amelioration of radiation effects was and still is tested in experimental systems, yet, only a small fraction of these approaches has so far been introduced into clinical studies. One advantage of most of the methods is that they may be effective even if the treatment starts way after the end of radiation exposure. For a clinical exploitation, hence, the availability of early indicators for the progression of subclinical damage in the individual patient would be desirable. Moreover, there is need to further investigate the molecular pathogenesis of normal tissue effects in more detail, in order to optimise biology based preventive strategies, as well as to identify the precise mechanisms of already tested approaches (e. g. stem cells).


2020 ◽  
Vol 20 (2) ◽  
pp. 130-145 ◽  
Author(s):  
Keywan Mortezaee ◽  
Masoud Najafi ◽  
Bagher Farhood ◽  
Amirhossein Ahmadi ◽  
Dheyauldeen Shabeeb ◽  
...  

Cancer is one of the most complicated diseases in present-day medical science. Yearly, several studies suggest various strategies for preventing carcinogenesis. Furthermore, experiments for the treatment of cancer with low side effects are ongoing. Chemotherapy, targeted therapy, radiotherapy and immunotherapy are the most common non-invasive strategies for cancer treatment. One of the most challenging issues encountered with these modalities is low effectiveness, as well as normal tissue toxicity for chemo-radiation therapy. The use of some agents as adjuvants has been suggested to improve tumor responses and also alleviate normal tissue toxicity. Resveratrol, a natural flavonoid, has attracted a lot of attention for the management of both tumor and normal tissue responses to various modalities of cancer therapy. As an antioxidant and anti-inflammatory agent, in vitro and in vivo studies show that it is able to mitigate chemo-radiation toxicity in normal tissues. However, clinical studies to confirm the usage of resveratrol as a chemo-radioprotector are lacking. In addition, it can sensitize various types of cancer cells to both chemotherapy drugs and radiation. In recent years, some clinical studies suggested that resveratrol may have an effect on inducing cancer cell killing. Yet, clinical translation of resveratrol has not yielded desirable results for the combination of resveratrol with radiotherapy, targeted therapy or immunotherapy. In this paper, we review the potential role of resveratrol for preserving normal tissues and sensitization of cancer cells in combination with different cancer treatment modalities.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3044-3044
Author(s):  
David Haan ◽  
Anna Bergamaschi ◽  
Yuhong Ning ◽  
William Gibb ◽  
Michael Kesling ◽  
...  

3044 Background: Epigenomics assays have recently become popular tools for identification of molecular biomarkers, both in tissue and in plasma. In particular 5-hydroxymethyl-cytosine (5hmC) method, has been shown to enable the epigenomic regulation of gene expression and subsequent gene activity, with different patterns, across several tumor and normal tissues types. In this study we show that 5hmC profiles enable discrete classification of tumor and normal tissue for breast, colorectal, lung ovary and pancreas. Such classification was also recapitulated in cfDNA from patient with breast, colorectal, lung, ovarian and pancreatic cancers. Methods: DNA was isolated from 176 fresh frozen tissues from breast, colorectal, lung, ovary and pancreas (44 per tumor per tissue type and up to 11 tumor tissues for each stage (I-IV)) and up to 10 normal tissues per tissue type. cfDNA was isolated from plasma from 783 non-cancer individuals and 569 cancer patients. Plasma-isolated cfDNA and tumor genomic DNA, were enriched for the 5hmC fraction using chemical labelling, sequenced, and aligned to a reference genome to construct features sets of 5hmC patterns. Results: 5hmC multinomial logistic regression analysis was employed across tumor and normal tissues and identified a set of specific and discrete tumor and normal tissue gene-based features. This indicates that we can classify samples regardless of source, with a high degree of accuracy, based on tissue of origin and also distinguish between normal and tumor status.Next, we employed a stacked ensemble machine learning algorithm combining multiple logistic regression models across diverse feature sets to the cfDNA dataset composed of 783 non cancers and 569 cancers comprising 67 breast, 118 colorectal, 210 Lung, 71 ovarian and 100 pancreatic cancers. We identified a genomic signature that enable the classification of non-cancer versus cancers with an outer fold cross validation sensitivity of 49% (CI 45%-53%) at 99% specificity. Further, individual cancer outer fold cross validation sensitivity at 99% specificity, was measured as follows: breast 30% (CI 119% -42%); colorectal 41% (CI 32%-50%); lung 49% (CI 42%-56%); ovarian 72% (CI 60-82%); pancreatic 56% (CI 46%-66%). Conclusions: This study demonstrates that 5hmC profiles can distinguish cancer and normal tissues based on their origin. Further, 5hmC changes in cfDNA enables detection of the several cancer types: breast, colorectal, lung, ovarian and pancreatic cancers. Our technology provides a non-invasive tool for cancer detection with low risk sample collection enabling improved compliance than current screening methods. Among other utilities, we believe our technology could be applied to asymptomatic high-risk individuals thus enabling enrichment for those subjects that most need a diagnostic imaging follow up.


1977 ◽  
Vol 86 (5) ◽  
pp. 661-666 ◽  
Author(s):  
Robert J. Carpenter ◽  
Robert J. Ryan ◽  
H. Bryan Neel ◽  
David R. Sanderson

Hematoporphyrin derivative (HpD) is one of several photodynamically active dyes that accumulate in tumor cells and can be used to differentiate neoplastic from normal tissue by violet light activation. Degree of tumor fluorescence was studied in relation to the nature of the hematoporphyrin compound, dose of HpD injected, route of injection, and intensity of activating light. Our studies indicate that HpD is not a chromatographically homogeneous material. Four components of HpD have been identified by thin-layer chromatography; their nature is not presently known. Pure HpD is the best agent for tumor fluorescence as compared with the components studied. Intravenous injection of HpD resulted in a more intense red-orange fluorescence than that after intraperitoneal injection. Fluorescence was more intense at the tumor periphery where tumor invaded normal tissues and around blood vessels. HpD injection of 0.002 mg/gm body weight induced more selective fluorescence of tumor than did 0.01 mg/gm. Microscopic examination of tumor showed fluorescence distributed throughout the cytoplasm. A fiberoptic bronchoscope attached to the Mayo-Baldes activating light source made possible induction of slight tumor fluorescence, but the intensity of activating light would not be adequate for clinical examination of the bronchial tree and detection of tumor.


2021 ◽  
Author(s):  
H. Robert Frost

AbstractThe genetic alterations that underlie cancer development are highly tissue-specific with the majority of driving alterations occurring in only a few cancer types and with alterations common to multiple cancer types often showing a tissue-specific functional impact. This tissue-specificity means that the biology of normal tissues carries important information regarding the pathophysiology of the associated cancers, information that can be leveraged to improve the power and accuracy of cancer genomic analyses. Research exploring the use of normal tissue data for the analysis of cancer genomics has primarily focused on the paired analysis of tumor and adjacent normal samples. Efforts to leverage the general characteristics of normal tissue for cancer analysis has received less attention with most investigations focusing on understanding the tissue-specific factors that lead to individual genomic alterations or dysregulated pathways within a single cancer type. To address this gap and support scenarios where adjacent normal tissue samples are not available, we explored the genome-wide association between the transcriptomes of 21 solid human cancers and their associated normal tissues as profiled in healthy individuals. While the average gene expression profiles of normal and cancerous tissue may appear distinct, with normal tissues more similar to other normal tissues than to the associated cancer types, when transformed into relative expression values, i.e., the ratio of expression in one tissue or cancer relative to the mean in other tissues or cancers, the close association between gene activity in normal tissues and related cancers is revealed. As we demonstrate through an analysis of tumor data from The Cancer Genome Atlas and normal tissue data from the Human Protein Atlas, this association between tissue-specific and cancer-specific expression values can be leveraged to improve the prognostic modeling of cancer, the comparative analysis of different cancer types, and the analysis of cancer and normal tissue pairs.


PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Christine Linard ◽  
Maâmar Souidi

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. Although the benefits of this treatment are well established, many patients experience distressing complications due to injury to normal tissue. These side effects are related to inflammatory processes, and they decrease therapeutic benefit by increasing the overall treatment time. Emerging evidence indicates that PPARs and their ligands are important in the modulation of immune and inflammatory reactions. This paper discusses the effects of abdominal irradiation on PPARs, their role and functions in irradiation toxicity, and the possibility of using their ligands for radioprotection.


2009 ◽  
Vol 8 (9) ◽  
pp. 747-751 ◽  
Author(s):  
Guoqing Zhang ◽  
Gregory M. Palmer ◽  
Mark W. Dewhirst ◽  
Cassandra L. Fraser

1960 ◽  
Vol 38 (8) ◽  
pp. 829-835 ◽  
Author(s):  
L. H. Burr ◽  
H. McLennan

The apparent extracellular volumes of the muscles from young normal and dystrophic mice have been estimated, using inulin dilution techniques. The inulin spaces were measured in the muscle both following injection of inulin in vivo and after soaking of excised tissues in a solution containing inulin. Comparisons were made between muscles of different size from the same animal as well as from different animals whose age, and consequently muscle size, varied. In all cases it has been found that the inulin space decreases with increasing muscle size. Similar results have been obtained by others with toad sartorii. The inulin space in muscles from dystrophic mice is larger than that of comparable normal tissues, and the dependence on muscle size, although similar to normal, is more pronounced. The results suggest that the dystrophic cells are permeable to inulin, and the question that some small permeability may be present also in normal tissue is considered.


2001 ◽  
Vol 17 (2) ◽  
pp. 41-48 ◽  
Author(s):  
Gregory J. Riggins

Tumor markers and antigens are normally highly expressed in malignant tissue, but not in the surrounding normal tissue. Serial Analysis of Gene Expression (SAGE) is a technology that counts mRNA transcripts and can be used to find those genes most highly induced in malignant tissues. SAGE produces a comprehensive profile of gene expression and can be used to search for tumor biomarkers in a limited number of samples. Public sources of SAGE data, in particular through the Cancer Genome Anatomy Project, increase the value of this technology by making a large source of information on many tumors and normal tissues available for comparison. Although the perfect tumor-specific gene does not exist, the differences in gene expression between tumor and normal can be exploited for therapeutic or diagnostic purposes.


Author(s):  
Xiaofei WU

Background: We aimed to investigate the expressions of miR-21 and miR-210 in the breast cancer tissue and their correlation with clinicopathological features and prognosis. Methods: A retrospective analysis was performed on 68 patients with breast cancer treated surgically in Wuhan General Hospital of Guangzhou Military in 2014-2015. The breast cancer tissue and the adjacent normal tissue were collected from the patients. Quantitative real-time PCR (qRT-PCR) was used to detect the expression levels of miR-21 and miR-210 in the breast cancer and adjacent normal tissues. Results: According to qRT-PCR, the expression levels of miR-210 and miR-21 in the breast cancer tissue were significantly higher than those in the adjacent normal tissue (P<0.05), which were significantly correlated with lymph node metastasis, clinical staging and differentiation of patients (P<0.05). miR-21 and miR-210 were significantly positive correlated in both breast cancer tissues and adjacent normal tissues (r=0.7014, 0.7502, P<0.001). The survival rate in the miR-210 high expression group was significantly lower than that in the miR210 low expression group (P<0.05), whereas there was no significant difference between the miR-21 high and low expression groups. Conclusion: miR-21 and miR-210 are highly expressed in the breast cancer tissue and significantly correlated with lymph node metastasis, clinical staging and differentiation. miR-210, the up-regulated expression of which is related to the poor prognosis of patients with breast cancer, may be a potential prognostic indicator for breast cancer, which can be used to judge the prognosis.


Sign in / Sign up

Export Citation Format

Share Document