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Gas plasmas, often referred to as cold physical plasma, are currently being investigated for their potential to serve as anticancer agents. Along similar lines, gas plasma-oxidized liquids as a carrier for reactive oxygen species have found their way into preclinical research. This review focuses on in vivo studies that utilized such gas plasma-oxidized liquids for cancer therapies. These preclinical tumor models, treatment modalities, and types of liquids that were used are summarized and critically discussed. Among these studies, significant results were observed, indicating the potential of oxidative liquids to serve as an anticancer treatment. However, several steps have to be taken to enhance the quality and translational capacities of this approach in order to gain clinical acceptance for possible future cancer therapies. The most crucial steps include not only a careful selection of suitable liquids, with respect to their approval as medical products, but also the consideration of orthotopic and immunocompetent animal tumor models. This would increase the relevance of such studies and simultaneously allow studying the contribution of the most potent of all anticancer effectors, the immune system.

The limitations and adverse effects of current anticancer therapies have prompted the exploration for novel and relatively safer anticancer drugs from natural sources. India has a rich diversity of venomous snake fauna and, over the past two decades, several studies have demonstrated the anticancer potential of Indian snake venoms and their isolated components in cancer cell lines and animal tumor models. Nevertheless, anticancer drug prototypes derived from Indian snake venoms are not currently clinically available. In this review, we discuss the anticancer potential of Indian snake venoms toxins, and provide a critical analysis of the associated investigations for the successful development of candidate venom toxins as anticarcinogenic drug prototypes in clinical settings.

Since its emergence, the application of CRISPR-associated nuclease 9 (Cas9) technology in cancer research has accelerated studies to investigate many aspects of treatment approaches for lung cancer, including the identification of target genes, construction of animal tumor models, and identification of drug resistance-related genes. Moreover, CRISPR/Cas9 can be used in gene therapy for lung cancer, specifically involving molecular targeted drugs and inhibitors. This article reviews the current landscape of CRISPR/Cas9 applications for lung cancer treatment as a basis for further studies. Given its promising performance, in-depth and systematic research on the application of CRISPR/Cas9 in lung cancer treatment will be necessary in future studies for its successful implementation in clinical practice.

Per- and polyfluorinated alkyl substances (PFAS) are ubiquitous, persistent, and toxic chemicals that pose public health risks. Recent carcinogenicity concerns have arisen based on epidemiological studies, animal tumor findings, and mechanistic data. Thousands of PFAS exist; however, current understanding of their toxicity is informed by studies of a select few, namely, perfluorooctanoic acid and perfluorooctanesulfonic acid. Hence, the computational, high-throughput screening tool, the US EPA CompTox Chemical Dashboard’s ToxCast, was utilized to explore the carcinogenicity potential of PFAS. Twenty-three major PFAS that had sufficient in vitro ToxCast data and covered a range of structural subclasses were analyzed with the visual analytics software ToxPi, yielding a qualitative and quantitative assessment of PFAS activity in realms closely linked with carcinogenicity. A comprehensive literature search was also conducted to check the consistency of analyses with other mechanistic data streams. The PFAS were found to induce a vast range of biological perturbations, in line with several of the International Agency for Research on Cancer–defined key carcinogen characteristics. Patterns observed varied by length of fluorine-bonded chains and/or functional group within and between each key characteristic, suggesting some structure-based variability in activity. In general, the major conclusions drawn from the analysis, that is, the most notable activities being modulation of receptor-mediated effects and induction of oxidative stress, were supported by literature findings. The study helps enhance understanding of the mechanistic pathways that underlie the potential carcinogenicity of various PFAS and hence could assist in hazard identification and risk assessment for this emerging and relevant class of environmental toxicants.

Animal tumor models provide invaluable insights on the host-tumor relationship to understand human tumor pathology so that defense strategies can be designed and optimized. This chapter describes the experiences of locoregional radionuclide cancer therapy using small animal models of mice and rats as well as large animal models of dogs to examine the advantages and disadvantages of these tumor models. Comparison of tumor growth curves allows the choice of optimal radionuclides for LRCT. Monitoring of radionuclides in LRCT also allows the prediction of efficacy. Individual animal monitoring can be accomplished using gamma cameras, PET scanners, or optical imaging. Surprising findings of immunity from subsequent inoculation of tumors are noted in rats cured from earlier tumor by LRCT. These interesting and surprise findings and their implications are also explored.

The routine methods used to treat oncological diseases have a number of drawbacks, including non-specific action and severe side effects for patients. Furthermore, tumor diseases are associated with a suppression of the immune system that often leads to the inefficiency of standard treatment methods. The development of novel immunotherapeutic approaches having specific antitumor action and that activate the immune system is of crucial importance. Vaccines based on dendritic cells (DCs) loaded with tumor antigens ex vivo that can activate antitumor cytotoxic T-cell responses stand out among different antitumor immunotherapeutic approaches. This review is focused on analyzing different methods of DC-based vaccine preparation and current research in antitumor DC-based vaccines using animal tumor models and in clinical trials.

Murine (mouse) mammary tumor models as analogs of human breast cancer are invaluable in cancer research but distinguishing murine sarcoma tumors from carcinoma tumors has been problematic. We present an image classification method with complete separation in projected parameter space.

// Fei Miao 1 , Mengmeng Zhang 1 , Yuechao Zhao 1 , Xiaolu Li 1 , Rongyan Yao 1 , Fan Wu 1 , Rong Huang 1 , Kai Li 1 , Shiying Miao 1 , Changwu Ma 4 , Hongge Ju 2, 3 , Wei Song 1 , Linfang Wang 1 1 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China 2 Department of Pathology, Baotou Medical College, Baotou 014040, China 3 Department of Pathology, The First Affiliated Hospital of Baotou Medical College, Baotou 014010, China 4 Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng 024000, China Correspondence to: Changwu Ma, email: docmachangwu@126.com Hongge Ju, email: juhongge1088@163.com Wei Song, email: songwei@ibms.pumc.edu.cn Keywords: colorectal cancer, EGFR, RHBDD1, AP-1, c-Jun Received: September 02, 2016 Accepted: January 24, 2017 Published: February 25, 2017 ABSTRACT Our previous study showed that RHBDD1 can activate the EGFR signaling pathway to promote colorectal cancer growth. In the present study, EGFR was decreased when RHBDD1 was knocked down or inactivated. Further analysis found that c-Jun and EGFR protein expression was decreased in RHBDD1 knockdown and inactivated cells. c-Jun overexpression in RHBDD1-inactivated cells rescued EGFR expression in a dose-dependent manner. RHBDD1 overexpression in RHBDD1-inactivated cells restored EGFR expression, but this effect was counteracted by c-Jun knockdown. Furthermore, EGFR and c-Jun were attenuated in the RHBDD1 knockdown and inactivated groups in animal tumor models. Tissue microarray assays demonstrated a correlation between RHBDD1 and EGFR in colorectal cancer patients. Therefore, our findings indicate that RHBDD1 stimulates EGFR expression by promoting the AP-1 pathway.

Many types of in vivo animal tumor models have been established. Among these, the chicken chorioallantoic membrane (CAM) model has proven to be particularly useful for transplanting various types of cancer cell lines or tumor tissues to study tumor formation, angiogenesis and metastasis. The CAM model is useful as an animal tumor model, as tumor could be rapidly formed. The tumor formation occurs in 3–4 days, much faster than in mouse models. In addition, the CAM model can be used for drug screening for cancer therapy. This chapter provides an overview of various types of CAM tumor models.

The goal of this chapter is to concisely introduce the most important noninvasive animal/preclinical imaging approaches that are used to image cancer models today. It is the scope of this chapter to discuss a subsection on models that are truly representative of the tumor microenvironment and highlight its applications, advantages, and translational challenges. Also, each modality’s salient advantages, considerations, and best applications will be discussed and demonstrated with examples from the literature. The altering nature of modeling cancer in mice will also be mentioned briefly, primarily through utilization of ectopic, orthotopic, patient-derived xenografts models with preclinical imaging which is well positioned to increase the use of these new, accurate, and resourceful modeling approaches.

Relapse or recurrence of colorectal cancer (CRC), which leads to metastasis, is one of the biggest clinical challenges, since mortality and morbidity are very high in this patient population. Despite advances in medicine, there is no cure in sight. Chemotherapy that produces high degree of toxicity has not been very successful. Various combinations of conventional chemotherapy and targeted therapeutics also show only limited benefit. Therefore, development of novel strategies to prevent/arrest the relapse and progression of malignancies, specifically CRC is of significant clinical importance. Newer therapeutic approaches are now under consideration with the advent of new chemotherapeutic or preventive agents and regimens. The validation of a nontoxic agent that could improve upon the current chemotherapeutic regimen would therefore be highly desirable. Testing these novel regimens in appropriate preclinical animal tumor models is of utmost importance for successful translation of these concepts. The current chapter summarizes the recent development of different chemopreventive strategies with natural agents, specifically curcumin and its analogues to combat the recurrence of CRC.

The study of animal models remains a cornerstone of preclinical cancer research. Recent advances in technology have led to the proliferation of animal imaging devices that are now integral to the study of cancer biology. Imaging is routinely used for the development and characterization of animal tumor models, measuring response to anticancer therapy, and for the detailed examination of individual molecular pathways within neoplastic tissue. The purpose of this chapter will be to provide an introduction to the most common imaging modalities used in contemporary oncologic investigation in order to help the reader determine if an imaging approach may complement their research goals.

Despite the broad rehabilitative potential of aquatic exercises, the relationship between aquatic exercise and the immune system has not been fully elucidated to date. In particular, there are few specific and delicate immunological approaches to the effect of water temperature on immunity. Thus, we examined the effect of water temperature on immunity during aquatic exercise. The animal tumor model was adopted to examine the impact of aquatic exercise at thermoneutral temperature (TT; 29°C) on immunity compared with aquatic exercise at body temperature (BT; 36°C). Tumor-bearing mice were made to swim in TT water or in BT water for 3 wk and immune cells and their functional activity were analyzed using FACS. Tumor growth was significantly suppressed in mice that exercised in TT than in BT water. The tumor control correlated with the increased number of NK (2-fold), γδT cells (2.5-fold), NKT (2.5-fold), and cytotoxic CD8+ T cells (1.6-fold), which play a critical role in anti-tumor immune responses. Furthermore, the functional activity was dramatically improved in the TT group, showing enhanced production of IFNγ in CD8+ T cells compared with the BT group. This study demonstrates that aquatic exercise in TT water may improve protective immune responses more effectively than in BT water. Although the effects of water temperature on immune function need further verification in humans, this study suggests that water temperature in human hydrotherapy may be important for improving immune function.

Bladder cancer is the most common type of tumor in the urogenital system. Approximately 75% of patients with bladder cancer present with non-muscle-invasive cancer, which is generally treated by transurethral resection and intravesical chemotherapy. In spite of different therapeutic options, there remains a very variable risk of recurrence and progression. Novel therapeutic methods of treating bladder cancer are urgently required. The exploration and preclinical evaluation of new treatments requires an animal tumor model that mimics the human counterpart. Animal models are key in bladder cancer research and provide a bridge to the clinic. Various animal bladder cancer models have been described to date, but the tumor take rate is reported to be 30-100%. Establishment of reliable, simple, practicable and reproducible animal models remains an ongoing challenge. The present review summarizes the latest developments with regard to the establishment of animal models and tumor evaluation.

The enhanced permeability and retention (EPR) of nanoparticles in tumors has long stood as one of the fundamental principles of cancer drug delivery, holding the promise of safe, simple and effective therapy. By allowing particles preferential access to tumors by virtue of size and longevity in circulation, EPR provided a neat rationale for the trend toward nano-sized drug carriers. Following the discovery of the phenomenon by Maeda in the mid-1980s, this rationale appeared to be well justified by the flood of evidence from preclinical studies and by the clinical success of Doxil. Clinical outcomes from nano-sized drug delivery systems, however, have indicated that EPR is not as reliable as previously thought. Drug carriers generally fail to provide superior efficacy to free drug systems when tested in clinical trials. A closer look reveals that EPR-dependent drug delivery is complicated by high tumor interstitial fluid pressure (IFP), irregular vascular distribution, and poor blood flow inside tumors. Furthermore, the animal tumor models used to study EPR differ from clinical tumors in several key aspects that seem to make EPR more pronounced than in human patients. On the basis of this evidence, we believe that EPR should only be invoked on a case-by-case basis, when clinical evidence suggests the tumor type is susceptible.

A scheme, named SUV_Shape, for the gross tumor volume (GTV) delineation on positron emission tomography (PET) images was designed by a numerical approximation method, and evaluated during this study. Twenty-one vacuous plastic balls of different shapes and sizes, their volumes ranged from 0.56 to 179.50 mL and were confirmed by a BL610 balance (Sartorius, Canada), consisted of four group models. Every group model was filled with a specific activity [18F]-FDG solution (55.1, 38.2, 23.7, and 36.3 kBq/mL) represented tumor, and fixed at the bottom of a barrel which was filled with unlike [18F]-FDG solution (5.4, 6.8, 8.1, and 4.0 kBq/mL, correspondingly) represented the background. The PET data of them were acquired by two-dimensional and three-dimensional mode in a PET/CT scanner (Discovery ST8, GE Healthcare, USA). The volume of each ball was measured by SUV_Shape, and the BL610 balance, labeled as GTVs and GTVt, respectively. Five rabbits implanted VX2 squamous carcinomas were acquired by [18F]-FDG PET/CT. These rabbits were mercy killed within 24 h after PET/CT acquisition. VX2 tumors were surgically removed, and their volumes were measured by SUV_Shape, and caliper, labeled as GTVs and GTVt. The Spearman’s ρ between GTVs and GTVt were done. The tumor-background ratios in four groups of phantom models were 10.3, 5.6, 2.9, and 9.0, respectively. The relationship between GTVt and GTVs for phantom models was significant (Spearman’s ρ > 0.95, P

Rhizoma Paridis saponins (RPS) with a good antitumor effect in clinical use showed low bioavailability and toxicity. Combination of Rhizoma Curcuma longa with RPS, which called LouHuang preparation (LH), not only overcame the RPS limitations but also improved its anticancer effect. The median lethal dose (LD₅₀) of LH in mice was 3410.9 mg/kg by oral acute toxicity test. LH relieved the inhibition of RPS on the gastric emptying (70.13 ± 4.80% vs. 49.12 ± 8.06%). As for the antitumor effect, the tumor weight/volume inhibition rate, tumor volume growth rate, and water/food efficiency ratio were calculated. LH had the highest inhibition ratio of 57.07 ± 2.97% for H22 model, 43.22 ± 0.72% for S180 model, and 46.8 ± 0.97% for EAC model, which were higher than RPS. Compared to ZiLongJin (ZLJ), a marked antitumor drug in China, LH also had the higher inhibition rate for tumor weight and tumor volume growth, which weaker than CTX. The water/food efficiency ratio reflected the difference of the quality life of the mice bearing tumor cells or not. CTX attenuated body weight gain and increased food efficiency ratio compared to control group. LH did not affect the body weight or water/food intake. The active part of LH was RPS and turmeric polysaccharides with the inhibition of 58% and 47% on H22 and S180 tumor models. The research provided theoretical and practical basis for LH application.

Preclinical imaging with radiolabeled probes became an integral part of the complex translational process that moves a newly developed compound from laboratory to clinical application. Imaging studies in animal tumor models may be undertaken to test a newly synthesized tracer, a newly developed drug or to interrogate, in the living organism, specific molecular and biological processes underlying tumor growth and progression. The aim of the present review is to outline the current knowledge and future perspectives of preclinical imaging in oncology by providing examples from recent literature. Among the biological processes and molecular targets that can be visualized with radiolabeled probes in animal tumor models, we focused on proliferation, expression of targets suitable for therapy, glycolytic phenotype, metastatic dissemination, tumor angiogenesis and survival. The major contribution of preclinical imaging emerging from these studies is the development and validation of imaging biomarkers that can be translated into the clinical context for patient selection and evaluation of tumor response to molecularly targeted agents.

Background and Objective: The hypoxia PET tracer, 1-[ 18 F]fluoro-3-(2-nitro-1Himidazol- 1-yl)-propan-2-ol ([ 18 F]FMISO) is the first radiotracer developed for hypoxia PET imaging and has shown promising for cancer diagnosis and prognosis. However, access to [ 18 F]FMISO radiotracer is limited due to the needed cyclotron and radiochemistry expertise. The study aimed to develop the automated production method on the [ 18 F]FMISO radiotracer with the novel fully automated platform of the BG75 system and validate its usage on animal tumor models. Method: [ 18 F]FMISO was produced with the dose synthesis cartridge automatically on the BG75 system. Validation of [ 18 F]FMISO hypoxia imaging functionality was conducted on two tumor mouse models (FaDu/U87 tumor). The distribution of [ 18 F]FMISO within tumor was further validated by the standard hypoxia marker EF5. Results: The average radiochemical purity was (99±1) % and the average pH was 5.5±0.2 with other quality attributes passing standard criteria (n=12). Overall biodistribution for [ 18 F]FMISO in both tumor models was consistent with reported studies where bladder and large intestines presented highest activity at 90 min post injection. High spatial correlation was found between [ 18 F]FMISO autoradiography and EF5 hypoxia staining, indicating high hypoxia specificity of [ 18 MF]FMISO. Conclusion: This study shows that qualified [ 18 F]FMISO can be efficiently produced on the BG75 system in an automated “dose-on-demand” mode using single dose disposable cards. The possibilities of having a low-cost, automated system manufacturing ([ 18 F]Fluoride production + synthesis + QC) different radiotracers will greatly enhance the potential for PET technology to reach new geographical areas and underserved patient populations.

Anticancer nanomedicine was coined to describe anticancer delivery systems such as polymer conjugates, liposomes, micelles, and metal nanoparticles. These anticancer delivery platforms have been developed with the enhanced permeability and retention (EPR) effect as a central mechanism for tumor targeting. EPR based nanomedicine has demonstrated, beyond doubt, to selectively target tumor tissues in animal models. However, over the last two decades, only nine anticancer agents utilizing this targeting strategy have been approved for clinical use. In this review, we systematically analyze various aspects that explain the limited clinical progress yet achieved. The influence of nanomedicine physicochemical characteristics, animal tumor models, and variations in tumor biology, on EPR based tumor targeting is closely examined. Furthermore, we reviewed results from over one hundred publications to construct patterns of factors that can influence the transition of EPR based anticancer nanomedicine to the clinic.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides critical information regarding tumor perfusion and permeability by injecting a T(1) contrast agent, such as Gd-DTPA, and making a time-resolved measurement of signal increase. Both temporal and spatial resolutions are required to be high to achieve an accurate and reproducible estimation of tumor perfusion. However, the dynamic nature of the DCE experiment limits simultaneous improvement of temporal and spatial resolution by conventional methods. Compressed sensing (CS) has become an important tool for the acceleration of imaging times in MRI, which is achieved by enabling the reconstruction of subsampled data. Similarly, CS algorithms can be utilized to improve the temporal/spatial resolution of DCE-MRI, and several works describing retrospective simulations have demonstrated the feasibility of such improvements. In this study, the fast low angle shot sequence was modified to implement a Cartesian, CS-optimized, sub-Nyquist phase encoding acquisition/reconstruction with multiple two-dimensional slice selections and was tested on water phantoms and animal tumor models. The mean voxel-level concordance correlation coefficient for Ak(ep) values obtained from ×4 and ×8 accelerated and the fully sampled data was 0.87±0.11 and 0.83±0.11, respectively (n=6), with optimized CS parameters. In this case, the reduction of phase encoding steps made possible by CS reconstruction improved effectively the temporal/spatial resolution of DCE-MRI data using an in vivo animal tumor model (n=6) and may be useful for the investigation of accelerated acquisitions in preclinical and clinical DCE-MRI trials.

Natural products, useful in preventing and/or treating various diseases, have been sought after throughout the man’s history. Despite some problems inherited from the natural source of glucans, there is extensive literature about their activities in animal tumor models. For the past 25 years, Japan has used several forms of mushroom-derived glucans in treating cancer patients. Additionally, close to twenty clinical trials are currently running in several countries, further suggesting the strong possibility of using glucans as an established anti-cancer drug.

Positron emission tomography (PET) is being increasingly applied to animal tumor models due to the need for proof-of-concept testing and preclinical efficacy studies of anticancer agents. Regardless of the nature of an experiment, investigators should carefully select a suitable animal tumor model as part of the experimental design. This review introduces sources of information and the guiding principles regarding applicability of various animal tumor models for PET in anticancer agent development especially for small animals.

It is virtually impossible to observe blood vessels by conventional x-ray imaging techniques without using contrast agents. In addition, such x-ray systems are typically incapable of detecting vessels with diameters less than 200 microm. Here we show that vessels as small as 30 microm could be detected using in-line phase-contrast x-ray imaging without the use of contrast agents. Image quality was greatly improved by replacing resident blood with physiological saline. Furthermore, an entire branch of the portal vein from the main axial portal vein to the eighth generation of branching could be captured in a single phase-contrast image. Prior to our work, detection of 30 microm diameter blood vessels could only be achieved using x-ray interferometry, which requires sophisticated x-ray optics. Our results thus demonstrate that in-line phase-contrast x-ray imaging, using physiological saline as a contrast agent, provides an alternative to the interferometric method that can be much more easily implemented and also offers the advantage of a larger field of view. A possible application of this methodology is in animal tumor models, where it can be used to observe tumor angiogenesis and the treatment effects of antineoplastic agents.

Black seeds, in some form or the other, have remained popular in folklore medicine throughout the history of mankind. This herb has been used for millenniums to strengthen the immune system, cleanse the body, purify the blood, protect against irritants, and support health longevity. Not only do the scriptures from three major religions of the world (Judaism, Christianity, and Islam) endorse their health benefits, the use of black seed oil has been emphasized in the Mesopotamian, Greek, Indus Valley, Egyptian, and other important civilizations. Despite the unequivocal medicinal use of black seeds since ancient times, little was known in terms of its major active ingredients. Modern molecular research has expanded the repertoire of biological effects elicited by these intriguing seeds compelling the research community to characterize the main element responsible for the health benefits. The development of high-performance purification techniques allowed the parsing of the constituents of Black seeds to a much deeper level. These studies have concluded in the identification of Thymoquinone as the major component in black seeds that is responsible for the various biological effects, particularly its anticancer mechanism. These findings drove intense research in different laboratories all across the globe leading to considerable enhancement of our knowledge of Thymoquinone’s primary as well as interacting mechanisms against cancer cells. Despite the encouraging laboratory results in cancer cell lines and preclinical efficacy in animal tumor models, a major problem associated with Thymoquinone is its poor bioavailability. This serves as a major caveat and is therefore the chief hurdle blocking its translation as a therapeutic agent in the clinic. In order to overcome this problem, a number of novel analogues of Thymoquinone have been developed recently that have shown superior pharmacokinetic properties. These analogues show early promise at least in the preclinical setting and provide confidence for their future incorporation into clinical practice as single agent or part of a combination regimen for cancer treatment. Through this chapter, we bring forth a historical perspective on the different major milestones in Black seed anticancer research. The current knowledge on the progress of black seed-derived anticancer agents is highlighted along with a forward-looking view as to where the Thymoquinone-related research field might be heading.

IL-15 is an immune-enhancing cytokine belonging to the IL-2 family, which supports survival, proliferation and functional activities of NK, NK-T, T and B cells. Moreover, IL-15 may support the growth and survival of different lymphoid malignancies, suggesting that targeting of the IL-15/IL-15R system or its downstream signaling cascade may result in therapeutic effects, in these tumors. On the other hand, given its immune-enhancing activities IL-15 has been considered a good candidate for cancer immunotherapy. Indeed, IL-15 or IL-15 super agonists have shown anti-tumor activity in several animal tumor models either alone or combined with other immune-enhancing molecules. Therefore, clinical trials of IL-15 or IL-15 super-agonists are ongoing in different cancers. Here we will summarize the biological features of the IL-15/IL-15R system and discuss its duality in tumor biology and the potential applications of IL-15 agonists and antagonists in cancer.

The hamster buccal pouch (HBP) carcinogenesis model is one of the most well-characterized animal tumor models used as a prelude to investigate multistage oral carcinogenesis and to assess the efficacy of chemointervention. Hamster buccal pouch carcinomas induced by 7,12-dimethylbenz[a]anthracene (DMBA) show extensive similarities to human oral squamous cell carcinomas. The HBP model offers a number of advantages including a simple and predictable tumor induction procedure, easy accessibility for examination and follow-up of lesions, and reproducibility. This model can be used to test both chemopreventive and chemotherapeutic agents.

Mumps virus belongs to the family of Paramyxoviridae and has the potential to be an oncolytic agent. Mumps virus Urabe strain had been tested in the clinical setting as a treatment for human cancer four decades ago in Japan. These clinical studies demonstrated that mumps virus could be a promising cancer therapeutic agent that showed significant antitumor activity against various types of cancers. Since oncolytic virotherapy was not in the limelight until the beginning of the 21(st) century, the interest to pursue mumps virus for cancer treatment slowly faded away. Recent success stories of oncolytic clinical trials prompted us to resurrect the mumps virus and to explore its potential for cancer treatment. We have obtained the Urabe strain of mumps virus from Osaka University, Japan, which was used in the earlier human clinical trials. In this report we describe the development of a reverse genetics system from a major isolate of this Urabe strain mumps virus stock, and the construction and characterization of several recombinant mumps viruses with additional transgenes. We present initial data demonstrating these recombinant mumps viruses have oncolytic activity against tumor cell lines in vitro and some efficacy in preliminary pilot animal tumor models.

A new, chemically induced animal tumor cell line (HeDe) was established and characterized by its property of causing aggressively growing tumors in specific strain of rats and changes in the chromatin structure. Results show that (1) the nuclear material in nuclei of normal resting (G0) hepatocytes consists mainly of decondensed veil-like chromatin, chromosomes being clustered in six lobular domains; (2) nuclei of HeDe cells contain primarily supercoiled chromatin; or (3) the nuclear material of tumor cells undergoes apoptosis seen as apoptotic bodies. Heterogeneity of chromatin structures was expressed as contour/area ratio and was nine times higher in apoptotic cells and two times higher in tumor cells compared to resting cells.

Vasoactive intestinal peptide (VIP) receptors are expressed abundantly on many types of tumors and, hence, radiolabeled VIP analogues are being explored for tumor imaging and therapy. Here, we report synthesis of three VIP analogues and their radiolabeling with 99m Tc via a novel tricarbonyl synthon. The radiolabeled product could be prepared in high yields (>95%) and stability. In vitro studies showed significant uptake of 99m Tc(CO) 3 -VP05 in human colon carcinoma cells. Biodistribution studies in animal tumor model showed 0.4–1% ID/g tumor uptake.

Homeodomain-containing transcription factors are the important regulators of multicellular organism's development. Plant transcription factors WOX and KNOX play the key role in meristem maintenance, controlling cell proliferation and preventing differentiation. The precise mechanism of WOX and KNOX action hasn't been well studied, however these transcription factors were shown to play the important role in plant hormones homeostasis, cytokinins in particular. Plant transcription factors of KNOX group demonstrate the similarities in structure and are supposed have the common origin with animal transcription factors of MEIS group. This review describes WOX and KNOX transcription factor families, their interaction with plant hormones. The role of homeodomain-containing transcription factors in plant and animal tumor formation is discussed.

Interleukins 18 and 21 have been described, and the effect of each upon immune response and experimental tumors in animals has been the subject of much recent work. Both interleukins have shown antitumor effects in animals, which in some models are striking for their duration, specificity, and ability to protect against rechallenge with the same tumor. These characteristics suggest immunologic involvement in the antitumor response, and several papers suggest involvement of both innate and adaptive immune mechanisms. Recent early phase I clinical trials in human cancer patients have demonstrated evidence of clinical response. This review discusses the biology, preclinical animal tumor model data, and early clinical trial findings.

The role of tea in protection against cancer has been supported by ample evidence from studies in cell culture and animal models. However, epidemiological studies have generated inconsistent results, some of which associated tea with reduced risk of cancer, whereas others found that tea lacks protective activity against certain human cancers. These results raise questions about the actual role of tea in human cancer that needs to be addressed. This article is intended to provide a better perspective on this controversy by summarizing the laboratory studies in animals and humans with emphasis on animal tumor bioassays on skin, lung, mammary glands and colon, and the molecular and cellular mechanisms affected by tea. Finally, a recent small pilot intervention study with green tea in smokers is presented.

Crown gall disease causes great economic losses worldwide by reducing crop yields and increases susceptibility to opportunistic pathogens. The anti-malarial Artesunate which is a derivative of artemisinin from Artemisia annua leaf and Garlic extracts known for their inhibitory and cytotoxic effects on the proliferation of human and animal tumor cells were investigated on rapidly dividing plant cells in Agrobacterium tumefaciens -induced crown gall tumor of tomato ( Solanum lycopersicum ) to determine their effects. Twenty four (24) tomato seedlings grown from seeds and divided into 4 treatment groups A, B, C and D were used for this study. Group A and B were inoculated with A. tumefaciens and treated with Artesunate and Garlic extract respectively for 3 weeks. Tomato seedlings of group C were the healthy seedlings that were not inoculated with A. tumefaciens and group D contains the seedlings that were inoculated with A. tumefaciens but not treated. Within two weeks of inoculation with A. tumefaciens , some of the diseased seedlings developed obvious galls (tumors) compared to the Artesunate and Garlic treated seedlings and the healthy seedlings. It was observed that Artesunate and Garlic extracts showed significant inhibition ( P ≤ 0.05) against gall (tumor) development. Artesunate and Garlic treated seedlings had better growth compared to the diseased seedlings. However, Garlic extract was observed to be more effective than Artesunate at inhibiting gall (tumor). This therefore confirmed the efficacy of garlic extracts and synthetic artesunate against crown gall disease of tomato. Keywords: Artesunate, Garlic, Crown gall tumor and Agrobacterium tumefaciens

Endoplasmic reticulum (ER) is a well organized membranous network, responsible for synthesis and folding of secretory and membrane proteins, lipid and sterol biosynthesis and intracellular calcium storage. Perturbations in ER lumen caused by depletion of Ca2+ levels, hypoxia, nutrient deprivation, affect the ER homeostasis, a condition known as an ER stress. In order to cope with this stress, cells have developed an orchestrated biochemical response, termed Unfolded Protein Response (UPR). Hypoxia, an ER stress inducer, is an important and unique characteristic of the solid tumor microenvironment, promotes resistance to radiotherapy and contributes to poor patient prognosis. Cancer cells overcome these stress conditions through activation the PERK-eIF2α arm of the UPR, leading to inhibition of global protein synthesis and cell survival. We hypothesize that the use of small molecule PERK inhibitors will decrease the survival of hypoxic cells and eventually sensitize them to irradiation. In this study we used highly radioresistant melanoma and head and neck squamous cell carcinoma cell lines B16F10-ova and SQ20B, under nomroxia and hypoxia, respectively. We used two specific PERK inhibitors (PERKi) and tested for their efficacy both in vitro and in vivo. Induction of ER stress in both cell lines, either by treatment with the pharmacologic agents thapsigargin (TG) and tunicamycin (TN), or by exposure to hypoxic conditions (0.2%), was evaluated by activation of PERK and its downstream targets. Pre-treatment of stressed B16F10-ova and SQ20B cells for 2h with PERKi (1μM), caused complete inhibition of PERK-eIF2a-ATF4-CHOP arm of the UPR. Moreover, both cell lines pre-treated with PERKi presented a significant decrease in survival fraction under ER-stress induced by TG (0.5μM) as well as under hypoxia (0.2%) along with increasing doses of irradiation (IR). For the in vivo experiments, nude and C57BL/6 mice were treated with either 100mg/kg of PERKi by oral gavage, twice a day for 3weeks, or IR or a combination of PERKi and IR. Mice treated with PERKi showed a small but not significant delay of tumor growth in both backgrounds of mice. However, combined treatment with IR (12 and 15Gy) caused a significant reduction of tumor volume as well as a delayed tumor growth which was significantly more pronounced in the immunocompetent mice. Data from flow cytometry analysis of one of the the PERKi+IR treated tumors from C57BL/6 mice showed that there is a significant infiltration of CD3+ cells as well as significant higher number of CD3+CD8+ cells compared to the untreated mice or mice treated with either PERKi or IR alone. Collectively, our results show that PERKi effectively reduces the survival of hypoxic B16F10-ova and SQ20B cells and sensitize them to IR in vitro and in tumors. Further experiments will clarify whether PERKi have a dual role on reducing the hypoxic fraction and direct recruitment of the cytotoxic T-cells. Citation Format: Ioannis Verginadis, Joel Encarnación, Souvik Dey, Constantinos Koumenis. Inhibition of PERK by small molecule inhibitors enhances the response to ionizing radiation in vitro and animal tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2017-4500

Indoleamine 2,3-dioxigenase 1 (IDO1) is the main enzyme that catalyzes the first, rate-limiting step of the so-called “kynurenine pathway”, i.e., the metabolic cascade that converts the essential amino acid L-tryptophan (Trp) into L-kynurenine (Kyn). IDO1, which is expressed constitutively by some tissues and in an inducible manner by specific subsets of antigen-presenting cells, has been shown to play a role in the establishment and maintenance of peripheral tolerance. At least in part, this reflects the capacity of IDO1 to restrict the microenvironmental availability of Trp and to favor the accumulation of Kyn and some of its derivatives. Also, several neoplastic lesions express IDO1, providing them with a means to evade anticancer immunosurveillance. This consideration has driven the development of several IDO1 inhibitors, some of which (including 1-methyltryptophan) have nowadays entered clinical evaluation. In animal tumor models, the inhibition of IDO1 by chemical or genetic interventions is indeed associated with the (re)activation of therapeutically relevant anticancer immune responses. This said, several immunotherapeutic regimens exert robust clinical activity in spite of their ability to promote the expression of IDO1. Moreover, 1-methyltryptophan has recently been shown to exert IDO1-independent immunostimulatory effects. Here, we summarize the preclinical and clinical studies testing the antineoplastic activity of IDO1-targeting interventions.

The potential of targeted delivery of chemotherapeutic drugs for the treatment of cancer has not yet been realized owing to the difficulty of delivering therapeutic concentrations to the target site. While in vivo studies in animal tumor models have produced very encouraging results, clinical studies with antibody-drug conjugates have been less successful. This paper will review the current status of the targeted delivery approach and analyze some of the reasons for the lack of success so far. Starting with a historical perspective, this review will end with a description of newer, more potent and specific antibody-drug conjugates, which behave like tumor-activated prodrugs that may yet fulfil the promise of the targeted delivery approach for the treatment of cancer.

Cancer-specific imaging remains a paramount challenge despite promise in early diagnosis, post-therapy monitoring as well as image-guided therapy of tumors. Achieving a broad and yet tumor-specific imaging efficacy presents a dilemma since conventional targeting of specialized cancer cell biomarkers (e.g. Her2/neu) often limits the outcome to a small subset of tumors. In this study, a more generalized strategy will be presented to achieve tumor-specific imaging by targeting universal tumor microenvironmental signals, namely the acidic extracellular pH (pHe) of tumors. This is accomplished by the development of ultra-pH sensitive (UPS) fluorescent nanoprobes, which can be turned ON/OFF within 0.20 pH unit with a large fluorescence activation ratio (>100-fold). These nanoprobes stay silent during blood circulation, but become activated inside tumors through non-linear amplification of tumor microenvironment signals. Broad tumor specificity was observed in various animal tumor models of diverse cancer genotypes. This nanoplatform opens up opportunities for image-guided surgery of tumors to improve resection accuracy.

This study compares the systemic and topical application of photofrin II and aminolevulinic acid as an intraoperative adjuvant therapy in the C3H mouse radiation-induced fibrosarcoma model. Dose-development and time-dependent studies were first conducted followed by intraoperative phototherapy studies with photofrin II and aminolevulinic acid. Study results clearly show that intraoperative phototherapy after aminolevulinic acid topical application is significantly more effective than treatment with photofrin II given intravenously or topically (p < 0.05) in this animal tumor model. The concept of topical application of photosensitizers and the rationale for intraoperative adjuvant phototherapy are discussed.