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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.

// 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.

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.

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.

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.

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.

Over the past decade much research has focused on understanding the molecular pathways that regulate the development of a tumor-associated vasculature. In 1999, Lyden and colleagues showed that mice deficient in one to three Id1 or Id3 alleles could not support the growth of tumor xenografts due to defects in tumor-associated angiogenesis. Three recently published manuscripts have now re-examined the role of Id genes in the development of a tumor-associated vasculature using more clinically relevant tumor model systems. Remarkably, all three studies have found strikingly different results compared to the original xenograft data published in 1999. Below we review the current understanding of the role of Id genes in the development of a tumor-associated vasculature given the most recent data and suggest ways in which animal tumor model systems might be put to better use to provide more clinically relevant information.

Disappointing results from most late-stage clinical trials of cancer therapeutics indicate a need for improved and more-predictive animal tumor models. This insufficiency of models, combined with the advent of a class of drugs that target the tumor microenvironment rather than the tumor cell, presents new challenges for designing and interpreting preclinical efficacy studies. A comparison of the clinical efficacy of anti-angiogenic drugs with their corresponding preclinical studies over the past two decades offers many lessons that can inform and improve the design of experiments in existing mouse models. In addition, technological and logistical advances in mouse models of human cancer over the past five years have the potential to increase the clinical translatability of animal studies.

A review of the different animal tumor model systems used for radiolabeled monoclonal antibody research is given. Problems within the field of radioimmunotargeting are presented, and the tumor models are discussed in relation to the types of problems which can be investigated, and the ability of the models to answer different questions.

Hypoxia is a clinically important component of the tumor microenvironment because it adversely affects progression, metastasis, response to chemoradiation therapy, and overall patient survival. Here, we describe how different animal tumor models of lung cancer can yield surprisingly different hypoxic profiles. Clin Cancer Res; 16(19); 4685–7. ©2010 AACR.

Udgivelsesdato: 2010-Oct Abstract Positron emission tomography (PET) allows non-invasive detection and mapping of tumor hypoxia. However, slow tracer kinetics and low resolution, results in limited tumor-to-normal tissue contrast and the risk of missing areas where hypoxic cells are intermixed with necrosis. The shape of tumor time activity curves (TACs), as deduced from dynamic scans, may allow further separation of tumors/tumor sub-volumes that are inseparable based on static scans. This study was designed to define the added value of dynamic scans. Material and methods. Three squamous cell carcinoma tumor models were grown in mice. Mice were injected with the (18)F-labeled PET hypoxia-tracer fluoroazomycin arabinoside (FAZA) and the immunologically-detectable hypoxia-marker pimonidazole, and PET scanned dynamically for three to six hours. Subsequently, microregional tracer retention (autoradiography) and the distribution of pimonidazole-retaining cells (immunohistology) and necrosis were analyzed in tumor tissue sections. Dynamic PET data were analysed based on a two-compartment model with irreversible tracer binding generating estimates of the putative hypoxia surrogate markers k(3) (tracer trapping rate constant) and K(i) (influx rate constant from plasma into irreversible bound tracer). Results/Discussion. High tumor-to-reference tissue ratios and a strong linear correlation (R∼0.7 to 0.95) between density of hypoxic cells and FAZA concentration was observed three hours after tracer administration, suggesting that late time PET images provides an accurate measure of hypoxia against which kinetic model estimates can be validated. Tumor TACs varied widely (ranging from distinctly wash-out to accumulative type) among tumor types although pimonidazole-stainings revealed extensive hypoxia in all models. Kinetic analysis of tumor sub-volumes showed that k(3) correlated poorly with late time FAZA retention regionally in two of the three tumor models. The influx rate constant K(i) displayed far less variability and correlated strongly with late time FAZA retention (hypoxia) in two of three tumor models, whereas a non-consistent relationship was observed in the last tumor model. Our study demonstrates the potential usefulness of dynamic PET, but also that a simple two-compartment model may be inappropriate in some tumor models.

An interstitial hyperthermia system operating at 27 MHz has been developed at the Dr. Daniel den Hoed Cancer Center. To test this system in combination with interstitial radiotherapy and to study the interactions of interstitial radiotherapy and interstitial hyperthermia, animal experiments were performed using rhabdomyosarcoma type R1 transplanted in the flanks of female Wag/Rij rats. Using the 27 MHz system, it appeared feasible to obtain hyperthermic temperatures. In this experiment a thermal dose of 44 degrees C for 30 minutes was delivered by controlling the temperature at the periphery of the tumor to 44 degrees C. The interstitial heating applicators were inserted in four standard afterloading catheters implanted with a fixed spacing of 7 mm; the same catheters were used for the radioactive sources for interstitial radiotherapy treatment following the interstitial hyperthermia sessions. Interstitial radiotherapy was given by means of four Ir192 wires with an average activity of 4.5.10(7) Bq/cm. Minimum tumor doses of 20 to 115 Gy with a mean dose rate of 47 cGy/hour were applied. Interstitial hyperthermia alone resulted in a growth delay (GD1) of 6 +/- 2 days without significant reduction of tumor volume. The 50% tumor cure dose after interstitial radiotherapy alone was 95 +/- 9 Gy. Combination of interstitial hyperthermia and interstitial radiotherapy resulted in reduction of the 50% tumor cure dose to 48 +/- 13 Gy. The dose-effect data for cure for these modalities are compared to existing data for external irradiation and external hyperthermia in the same tumor model. It was found that the addition of hyperthermia to different modes of irradiation, that is, either to single dose or protracted radiotherapy, results in a common level of radiosensitivity through impaired repair of sublethal damage. This study demonstrates the feasibility of the 27 MHz heating system in achieving hyperthermic temperatures; in the combined modality experiments a thermal enhancement factor of 2.0 +/- 0.3 (mean +/- standard deviation) was observed.

Aging of the immune system is associated with a dramatic reduction in responsiveness as well as functional dysregulation. This deterioration of immune function with advancing age is associated with an increased incidence of cancer. Although there is a plethora of reports evaluating the effect of immunotherapy in stimulating antitumor immune responses, the majority of these studies do not pay attention to the effect aging has on the immune system. Studies from our group and others indicate that immunotherapies could be effective in the young, are not necessarily effective in the old. To optimally stimulate an antitumor immune response in the old, it is necessary to (1) identify and understand the intrinsic defects of the old immune system and (2) use relevant models that closely reflect those of cancer patients, where self-tolerance and aging are present simultaneously. The present review summarizes some defects found in the old immune system affecting the activation of antitumor immune responses, the strategies used to activate stronger antitumor immune response in the old and the use of a tolerant animal tumor model to target a self-tumor antigen for the optimization of immunotherapeutic interventions in the old.

The major shift today has been away from nonspecific compounds acting on immune mechanisms to using biologics which have specific, defined roles in acting on the immune response. The field of biologic response modification is progressing very rapidly. New peptides are being identified, as are receptors for these peptides, autocrines, lymphokines, cytokines, growth factors, differentiation factors, hormones, and so on-all of which will control body function, cell populations, and cell to cell interactions. This rapidly advancing area of research in cancer biology and cancer therapy may hold the key to the future of successful therapy.

This review summarizes clinical experience with infectious disease vaccines and data from animal tumor models that support a paradigm shift for cancer vaccines from therapeutic to prevention applications.

BACKGROUND The goal of the current study was to analyze the combined effect of bisphosphonates (BPs) and irradiation on remineralization and restabilization of osteolytic bone metastases in an animal tumor model. METHODS Bone metastases were induced in male Wistar rats via intraosseous injection of the Walker carcinosarcoma 256B cell line into both proximal tibia metaphyses on Day 1 of the study. Three treatment groups were analyzed. All animals received a single radiation dose of 17 grays (in the form of 6-megaelectron-volt electrons) on Day 7 and were sacrificed on Day 49. Group 1 (the control group) was treated with irradiation only. Groups 2 and 3 received additional BPs (clodronate; daily intraperitoneal injection dose, 20 mg/kg per day). In Group 2, BPs were given before irradiation, on Days 3–6; this schedule later was referred to as early BP treatment. In Group 3, BPs were administered simultaneously with irradiation, on Days 7–10; this schedule later was referred to as simultaneous BP treatment. The endpoints of the study were bone density and microstructural parameters of bone on Day 49. Bone density was measured using X-ray absorption. Microstructural parameters of bone were assessed using histomorphometry. A total of thirty tibiae were analyzed in each group. RESULTS After irradiation, bone density was significantly higher among animals in the early BP treatment group compared with those in the control group and those in the simultaneous BP treatment group (P = 0.001). Histomorphometric analysis of bone showed significantly better-preserved (P < 0.001) microstructural parameters (bone area, trabecular number, and trabecular separation) in the early BP treatment group compared with the control and simultaneous BP treatment groups. CONCLUSIONS Early BP administration in combination with irradiation led to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model. Cancer 2003;98:1318–24. © 2003 American Cancer Society. DOI 10.1002/cncr.11646

Gossypol, a polyphenolic compound extracted from cotton plants, shows promise for use as a male contraceptive, as well as a treatment for gynecological disorders, cancer, and certain microbial diseases. Before gossypol can be considered safe for widespread human use, particularly by healthy people of childbearing age, its effect on normal genetic processes should be understood. Characterization of gossypol's genotoxic potential has not been approached systematically, although numerous clinical and laboratory studies have addressed issues relating to genetic effects of gossypol. This review summarizes results of relevant studies and offers recommendations for the emphasis of future efforts to understand gossypol's genotoxicity potential. Evidence suggesting that gossypol has any genotoxic effects in mammals under normal physiologic conditions so far is weak, at best. However, several unresolved issues that are important for establishing long-term genetic safety of gossypol were uncovered by this analysis. These include the need for a better understanding of the significance of weak increases in SCE frequency seen in a number of laboratory exposure studies, and more definitive, comprehensive animal tumor bioassay data.

A number of reports indicate that fish n-3 PUFA inhibit the development, growth and progression of several experimental tumors. There emerges a pattern of complex and diverse biochemical actions of n-3 PUFA in different animal tumor models, from the studies undertaken to date to evaluate the underlying mechanisms. These findings, along with the recent epidemiological evidence of an inverse correlation between fish intake and incidence of some human cancers, makes it worthwhile to determine the role of n-3 PUFA in cancer.

One way to deliver high doses of radiation to deep seated tumors without damaging the surrounding tissue is by interstitial techniques. This is commonly applied clinically; however, biological data of tumor response to interstitial low-dose-rate gamma irradiation are scarce. Therefore, we have studied the response of rhabdomyosarcoma R1 tumors implanted in the flanks of female Wag/Rij rats using an interstitial Ir 192 afterloading system. A template was developed by which four catheters can be implanted in a square geometry with a fixed spacing. Subsequently four Ir 192 wires of 2 cm length each are inserted. For dose prescription the highest isodose enveloping the tumor volume was chosen. Interstitial irradiation was performed using tumor volumes of 1500–2000 mm 3 . A range of minimum tumor doses of 20 up to 115 Gy were given at a mean dose-rate of 48 cGy/hr. Dose-effect relations were obtained from tumor growth curves and tumor cure data, and compared to data from external irradiation. The dose required for 50% cures with interstitial irradiation (TCD50) appears to be 95 ± 9 Gy. The TCD50 for low-dose-rate interstitial gamma irradiation is 1.5 times the TCD50 for single dose external X ray irradiation at high dose rates, but is comparable to the TCD50 found after fractionated X ray irradiation at high dose rate. Sham treatment of the tumors had no effect on the time needed to reach twice the treatment volume. The growth rate of tumors regrowing after interstitial radiotherapy is not markedly different from the growth rate of untreated (control) tumors (volume doubting time 5.6 ± 1 day), in contrast to the decreased growth rate after external X ray irradiation. It is argued that the absence of a clear tumor bed effect may be explained by some sparing of the stroma by the low-dose-rate of the interstitial irradiation per se as well as by the physical dose distribution of the interstitial Ir 192 sources, giving a relative low dose of radiation to the surrounding normal tissues.

The effect of cancer treatment by ultrasound-induced hyperthermia in domestic pets was evaluated by computed tomography (CT) regarding changes in tumor volume and x-ray attenuation after intravenous contrast material. CT scanning is more accurate in measuring tumor volume than estimates after surface measurements. A decrease inn tumor volume and x-ray attenuation after contrast medium seems to be a valuable index of tumor response to hyperthermia.

For mst chemicals, human risk assessment begins when a significant number of cancers appear in a bioassay in which animals are exposed to the chemical in question. The assumption is made that any substance capable of causing cancer in animals can also cause cancer in humans. However, this attitude, as far as risk assessment is concerned, may become modified by estimates of sensitivity to carcinogenesis for animals versus humans, by the significance of animal tumor types and, possibly, by the development of an operational definition of a threshold. Risk/benefit considerations are appropriate but rest on scanty data. For the present, models for the prediction of human cancer following exposure to known animal carcinogens must be conservative and based on a zero threshold.

We were unable to maintain fragments of human tumor on the mucosal surface of isolated dog ileum as described by Folkman. With a radical modification of Folkman's technique we have been able to maintain HeLa cells injected submucosally. Modifications of the technique included a change in the perfusate, the gas mixture, and the oxygenator. Evidence of invasion by the HeLa cells was observed. On the basis of our present experience, the isolated dog ileum may be a satisfactory method of studying the behavior of various animal tumor systems, clones of human cells previously established in tissue culture, and perhaps fragments of biopsy specimens of human tumor.

IONIZING irradiation has an important role today in cancer therapy, both as an adjunct to surgery and as a primary treatment. Methods of increasing the effectiveness of irradiation have been sought, and numerous studies have been carried out in an attempt to elucidate the factors which alter the radiosensitivity of tumor cells (1). The amount of oxygen available to tissues at the time of irradiation is recognized as an important factor in their radiosensitivity. The radiosensitizing effect of oxygen on normal tissue is well documented (3-5) (Fig. 1). The premise that anemia decreases tissue radiosensitivity has long been accepted by radiotherapists, and correction of the anemia has been recommended as a means of increasing the effectiveness of irradiation (7). This concept is based upon an assumed correlation between anemia and reduced tissue oxygen tension. The present study was undertaken to assess the effect of anemia on the radiosensitivity of animal tumor tissue. Material and Methods New Zealand whit...

Hyperthermia induced by a microwave source (2,450 MHz) was used alone and in combination with photodynamic therapy (PDT) to treat the SMT-F, EMT-6, and RIF animal tumors in vivo. PDT was administered using either Photofrin I or II as the photosensitizer and an argon-pumped tunable dye laser (630 nm) as the light source. Greater than additive increases in long-term tumor control were achieved when hyperthermia was given immediately post-PDT in the SMT-F and RIF tumor systems. Only additive (or independent) increases in tumor control were achieved when hyperthermia was given immediately before PDT in all these tumor systems and when heat was applied post-PDT using the EMT-6 tumor. In a series of experiments using the SMT-F tumor, it was observed that decreases in PDT drug or light doses could be offset (in terms of tumor control) by the addition of a subsequent heat treatment. This result, along with others presented, indicates the clinical potential of PDT and hyperthermia as adjuvant cancer modalities.

A formulation of 14C-lomustine in propylene glycol-ethanol (4:1) was administered intravenously to rats infiltrated with glioma tumors of the astrocytic series (RT6). The organ and tumor distribution of this agent was followed at 1, 4, 12, and 24 hr. Rapid blood disappearance (0-1 hr) of the label concomitant with an increase in all organs except the lung, muscle, and brain was observed. Only the blood, liver, and muscle contained greater than 1% of the dose after 24 hr. The bladder, liver, small bowel, and kidneys concentrated the highest percentages throughout the study. The distribution of 14C-lomustine in the tumor relative to the brain, muscle, and blood showed a maximum 4-12 hr after administration.

The ability of animal tumor cells to repair potentially lethal damage was studied in vivo. Fifth-generation isotransplants of a spontaneous mouse squamous-cell carcinoma were irradiated under tourniquet-induced hypoxia or in air. Tumors were removed either immediately or 6 hours after irradiation and dose-response curves were determined by TD50 assays. Repair was attributed to cells in the hypoxic cell component for animals irradiated in air. Extensive repair was also noted for those irradiated under hypoxic conditions. Implications of these results are discussed.

The problem of applying experimental tumor studies to clinical cancer therapy is a complex one. The radiotherapy literature contains many examples of premature efforts to apply laboratory observations to the clinic, and many examples of failures to adequately consider animal tumor observations in the design of clinical studies. This review covers three areas: tumor hypoxia, where clinical trials based on animal tumor data have been conducted with radiosensitizers, hyperbaric oxygen, and systemic oxygen carriers; dose fractionation, where current trials of hyperfractionation are based in part on animal tumor studies; and chemo-radiotherapy, where clinical trials are only beginning to exploit concepts developed in animal tumor systems. The use of animal tumor systems extends past the screening of new agents. Animal tumor models can be used in biological, physiological, pharmacological studies to elucidate the biological factors influencing the efficacy of therapeutic agents. Tumor studies can be combined with studies of normal tissues to predict the toxicities to be anticipated in clinical trials, and to assess the potential for therapeutic gain. Animal studies can also provide data whic are useful in designing optimal clinical trials of new agents and maximizing the potential for successful clinical application of new approaches. In general, it is not possible to apply specific laboratory data directly to man. To translate, rather than transpose, information from the laboratory to the clinic, the model studies must be directed at evaluating principles, rather than merely quantifying results. Only through studies of mechanisms, by designing experiments to test or refute a hypothesis, will it be possible to apply model studies to man.

In vitro and in vivo results suggest that sodium ascorbate (vitamin C) could be useful in the management of neoplasms provided it is used on a biological rationale. Vitamin C can exert multiple mechanisms of action depending upon the cell type and experimental conditions. Vitamin C may kill certain tumor cells, may increase the cell killing effect of certain tumor therapeutic agents and may stimulate the host's immune system against the residual tumor cells. In vitro data also suggest that the irrational use of vitamin C in the management of neoplasms could be ineffective and even harmful. Further study on the effects of vitamin C in combination with tumor therapeutic agents must be done, using animal tumor models before assaying its role in the management of human neoplasms.

In a series of 6 experiments with CD8F1 mice with spontaneous mammary adenocarcinomas Sugiura noted by macrovisual observation with some histology an overall average of 21% of mice with lung metastases when treated with 1,000–2,000 mg/kg/day of amygdalin compared with 90% of the control mice. The significance attributed to those early observations is seriously challenged by the negative findings of 3 independent investigators, by 2 out of 3 negative cooperative experiments in which Sugiura participated, and particularly by the blind experiment in which he and others under blind readings found no anticancer activity. Treatment of Swiss albino mice showed no destructive effect upon their spontaneous mammary adenocarcinomas. Of the treated mice, 22% were found by macrovisual observation to have lung metastases while 91% were noted among the controls. The results are subject to questions raised in the discussion. Amygdalin at 2,000 mg/kg/day was ineffective both in treating and preventing the development of spontaneous leukemia in AKR mice. At 1,000 mg/kg/day it was not found effective in preventing or significantly delaying the development of spontaneous mammary tumors in CD8F1 mice. In summary, we do not have evidence to support taking amygdalin to clinical trial, although other considerations may require that one be conducted.

Discriminant analysis has been used to study the data for naphthoquinones as antitumor agents in three different animal tumor systems. In each case the most significant variables for classifying the compounds into two groups according to their antitumor activities were determined by a stepwise procedure. The usefulness of discriminant analysis in the design of drugs is discussed.

The effect of Levamisole was studied in an animal model of Wilms’ tumor. No tumoridical effect of Levamisole could be documented in this tumor model, and no effect was shown on prevention of tumor, when Levamisole was given before tumor implantation. In previous experience with Wilms’ tumor model, a good correlation between the human and animal tumor was found in regard to treatment with different drugs. The fact that Levamisole had no effect on our animal model and its reported immunosuppressive effect at some doses, should be considered in planning clinical trials.