Mouse Model Of Human Cancer Research Articles

Salmonella typhimurium A1-R effectively targets human-patient pancreatic tumorgrafts in nude mice.

e22012 Background: Genetically-modified Salmonella typhimurium A1-R selectively targets tumors of cancer in mouse models of human cancer. The aim of this study was to determine the efficacy S. typhimurium A1-R on human-patient pancreatic tumorgrafts growing orthothopically in nude mice. Methods: Pancreatic-cancer-patient tumor specimens were initially established subcutaneously in NOD/SCID mice immediately after surgery. The patient tumors were then harvested from NOD/SCID mice and passed orthotopically in transgenic nude mice, expressing fluorescent proteins in order for the tumors to acquire fluorescent stroma for imaging. After confirmation of tumor growth by fluorescence imaging, the nude mice were treated in the following groups: (1) 5-fluorouracil (5-FU) (10 mg/kg, ip); (2) cisplatin (CDDP) (10 mg/kg, ip); (3) gemcitabine (GEM) (150 mg/kg, ip); (4) S. typhimurium A1-R (1.5x108 cfu/body, ip); and (5) PBS (vehicle/control) (ip). Control, 5-FU, CDDP, GEM and S. typhimurium A1-R injections were performed on a weekly basis from day-21 after tumor implantation for 4 weeks. Animals were sacrificed at 7 weeks, and tumors were harvested for analysis. Each treatment arm involved 5 tumor-bearing mice. Results: No significant effects on body weight, morbidity, or severe toxicities were observed in any treatment arm. The tumor weight of each group was as follows: (1) 5-FU, 0.044 ± 0.027g; (2) CDDP, 0.04 ± 0.032g; (3) GEM, 0.058 ± 0.051g; (4) S. typhimurium A1-R, 0.106 ± 0.038g; and (5) PBS control, 0.258 ± 0.209g. S. typhimurium A1-R treatment significantly reduced the tumor weight compared to control treatment (p = 0.011), as did the other treatments including 5-FU (p = 0.005), CDDP (p = 0.004), and GEM (p = 0.001). Conclusions: S. typhimurium A1-R treatment was effective on human pancreatic tumorgrafts and should be tested in combination with chemotherapy.

Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer

Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex-forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region. The TFO-directed UDS facilitated incorporation of the antimetabolite, gemcitabine (GEM), into the damaged oncogene, thereby potentiating the anti-tumor activity of GEM. Mice bearing COLO 320DM human colon cancer xenografts (containing amplified c-MYC) were treated with a TFO targeted to c-MYC in combination with GEM. Tumor growth inhibition produced by the combination was significantly greater than with either TFO or GEM alone. Specific TFO binding to the genomic c-MYC gene was demonstrated, and TFO-induced DNA damage was confirmed by NBS1 accumulation, supporting a mechanism of enhanced efficacy of GEM via TFO-targeted DNA damage-induced UDS. Thus, coupling antimetabolite chemotherapeutics with a strategy that facilitates selective targeting of cells containing amplification of cancer-relevant genes can improve their activity against solid tumors, while possibly minimizing host toxicity.

Cancer of mice and men: old twists and new tails

In this review we set out to celebrate the contribution that mouse models of human cancer have made to our understanding of the fundamental mechanisms driving tumourigenesis. We take the opportunity to look forward to how the mouse will be used to model cancer and the tools and technologies that will be applied, and indulge in looking back at the key advances the mouse has made possible.

Complexity of cancer stem cells

Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy-based model in which cancer stem cells (CSCs) have the ability both to self-renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications.

Preclinical Magnetic Resonance Imaging and Systems Biology in Cancer Research: Current Applications and Challenges

Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating invivo imaging and therapeutic response data with exvivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy.

Investigation of Radiation Therapy Response Enhancement of DC Magnetic Fields

Purpose/Objective(s): H-NOX proteins are nitric-oxide-neutral oxygen carriers that address a key limitation of radiation therapy (RT) efficacy in solid tumors: hypoxia. Unlike previous hemoglobin-based oxygen carriers, H-NOX do not scavenge circulating nitric oxide, and thus are not associated with hypertensive or renal side effects. Additionally, H-NOX carriers are tuned to transport oxygen through normoxic regions of tumors and release oxygen deep within hypoxic zones within tumors. This combination of features represents a significant advance in the use of oxygen carriers as radiosensitizers. The aim of this study is to determine if H-NOX is able to penetrate, oxygenate, and radiosensitize an orthotopic mouse model of human cancer. Materials/Methods: To evaluate H-NOX biodistribution, mice bearing orthotopic human luciferase-modified tumors were infused by tail vein with fluorescently-labeled H-NOX, and imaged using a live-animal fluorescent imager. H-NOX localization was confirmed by immunohistochemistry (IHC). A separate cohort of tumor-bearing mice received infusions of unlabeled H-NOX, followed by pimonidazole injections for analysis of hypoxia reduction in tumor sections by IHC. To evaluate radiosensitization, tumor-bearing mice received intravenous injections of H-NOX prior to 3 fractions of RT (2 Gy/dose). Tumor growth was monitored by bioluminescence imaging, and mice were monitored for overall survival. Statistical analyses were conducted through the use of two-tailed t-tests (tumor growth delay) and the log-rank test (survival analysis). Results: After intravenous injection, H-NOX protein was able to localize to orthotopic tumors, and deliver sufficient oxygen to reduce hypoxia, as determined by a w60% decrease in pimonidazole staining. Three doses of H-NOX protein, when given before RT, were able to significantly slow tumor growth (p Z 0.039, RT v. RT + H-NOX) and significantly extend overall survival (p Z 0.025, RT v. RT + H-NOX), compared to mice receiving RT alone. Conclusions: H-NOX protein readily accumulates in orthotopic tumors after intravenous injection. Once at the site of action, H-NOX is capable of delivering sufficient amounts of oxygen to reduce hypoxia and confer radiosensitization in an orthotopic mouse model of human cancer. Future studies will further characterize the molecular mechanisms responsible for radiosensitization and develop a lead candidate for clinical trials. Author Disclosure: L. Serwer: A. Employee; Current Omniox Employee. E. Harris: A. Employee; Current Omniox Employee. J. Romero: A. Employee; Current Omniox Employee. A. Davis: A. Employee; Current Omniox Employee. G. Kapp: A. Employee; Current Omniox Employee. R. Santos: None. T. Ozawa: None. S. Cary: Q. Leadership; Omniox CEO. C. James: None.

In Vivo Investigation of Nonthermal Pulsed Focused Ultrasound for Prostate and Breast Cancer Therapy

Purpose/Objective(s): H-NOX proteins are nitric-oxide-neutral oxygen carriers that address a key limitation of radiation therapy (RT) efficacy in solid tumors: hypoxia. Unlike previous hemoglobin-based oxygen carriers, H-NOX do not scavenge circulating nitric oxide, and thus are not associated with hypertensive or renal side effects. Additionally, H-NOX carriers are tuned to transport oxygen through normoxic regions of tumors and release oxygen deep within hypoxic zones within tumors. This combination of features represents a significant advance in the use of oxygen carriers as radiosensitizers. The aim of this study is to determine if H-NOX is able to penetrate, oxygenate, and radiosensitize an orthotopic mouse model of human cancer. Materials/Methods: To evaluate H-NOX biodistribution, mice bearing orthotopic human luciferase-modified tumors were infused by tail vein with fluorescently-labeled H-NOX, and imaged using a live-animal fluorescent imager. H-NOX localization was confirmed by immunohistochemistry (IHC). A separate cohort of tumor-bearing mice received infusions of unlabeled H-NOX, followed by pimonidazole injections for analysis of hypoxia reduction in tumor sections by IHC. To evaluate radiosensitization, tumor-bearing mice received intravenous injections of H-NOX prior to 3 fractions of RT (2 Gy/dose). Tumor growth was monitored by bioluminescence imaging, and mice were monitored for overall survival. Statistical analyses were conducted through the use of two-tailed t-tests (tumor growth delay) and the log-rank test (survival analysis). Results: After intravenous injection, H-NOX protein was able to localize to orthotopic tumors, and deliver sufficient oxygen to reduce hypoxia, as determined by a w60% decrease in pimonidazole staining. Three doses of H-NOX protein, when given before RT, were able to significantly slow tumor growth (p Z 0.039, RT v. RT + H-NOX) and significantly extend overall survival (p Z 0.025, RT v. RT + H-NOX), compared to mice receiving RT alone. Conclusions: H-NOX protein readily accumulates in orthotopic tumors after intravenous injection. Once at the site of action, H-NOX is capable of delivering sufficient amounts of oxygen to reduce hypoxia and confer radiosensitization in an orthotopic mouse model of human cancer. Future studies will further characterize the molecular mechanisms responsible for radiosensitization and develop a lead candidate for clinical trials. Author Disclosure: L. Serwer: A. Employee; Current Omniox Employee. E. Harris: A. Employee; Current Omniox Employee. J. Romero: A. Employee; Current Omniox Employee. A. Davis: A. Employee; Current Omniox Employee. G. Kapp: A. Employee; Current Omniox Employee. R. Santos: None. T. Ozawa: None. S. Cary: Q. Leadership; Omniox CEO. C. James: None.

Novel Oxygen Carrier Proteins, H-NOX, Reduce Tumor Hypoxia and Act as Radiosensitizers in an Orthotopic Mouse Model of Human Cancer

Novel Oxygen Carrier Proteins, H-NOX, Reduce Tumor Hypoxia and Act as Radiosensitizers in an Orthotopic Mouse Model of Human Cancer

Imaging mitochondrial redox potential and its possible link to tumor metastatic potential.

Cellular redox states can regulate cell metabolism, growth, differentiation, motility, apoptosis, signaling pathways, and gene expressions etc. A growing body of literature suggest the importance of redox status for cancer progression. While most studies on redox state were done on cells and tissue lysates, it is important to understand the role of redox state in a tissue in vivo/ex vivo and image its heterogeneity. Redox scanning is a clinical-translatable method for imaging tissue mitochondrial redox potential with a submillimeter resolution. Redox scanning data in mouse models of human cancers demonstrate a correlation between mitochondrial redox state and tumor metastatic potential. I will discuss the significance of this correlation and possible directions for future research.

Modeling and predicting clinical efficacy for drugs targeting the tumor milieu

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.

Abstract 2678: Traditional Chinese Medicine (TCM) in combination with S. typhimurium A1-R for cancer treatment

Abstract Traditional Chinese Medicine (TCM) has long shown promise for the treatment of cancer. We have previously developed a bacterial cancer therapy strategy using the genetically-engineered strain, Salmonella typhimurium A1-R, which is auxotrophic for arg and leu, which attenuates growth in normal tissue but allows high tumor virulence. S. typhimurium A1-R is effective against metastatic human prostate, breast, and pancreatic cancer cell lines as well as osteosarcoma, fibrosarcoma, and glioma cell lines in clinically-relevant nude-mouse and syngeneic-mouse models. The current study evaluated TCM as combination treatment during bacterial therapy in metastatic mouse models of human cancer. TCM prevented hemorrhagic spots on the skin, liver, and spleen after bacterial infection. Fur discoloration and reduced activity was also observed in mice treated with S. typhimurium A1-R. These symptoms were ameliorated when bacterial treatment was combined with TCM. In a syngeneic lung cancer metastatic model in immunocompetent mice, the combination of TCM and S. typhimurium A1-R enabled S. typhimurium to be safely administered at a dose of 2×105 CFU twice a week i.v. in immunocompotent mice with increased treatment efficacy compared to monotherapy with S. typhimurium A1-R. The results of the present study suggest that combination of S. typhimurium A1-R and TCM has important potential for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2678. doi:1538-7445.AM2012-2678

Abstract 5266: Anti-cancer drug development using bioactive compounds from Tillandsia recurvata in mouse models of human cancer

Abstract Background: The Jamaican Tillandsia recurvata species is being fully investigated scientifically for medicinal properties and has demonstrated powerful anti-cancer properties in vitro and in vivo. Aim The scope of this study was to investigate the anti-tumor and anti-HIV effects of Ball Moss extracts, isolates and synthesized molecules both in vivo and in vitro in five histogenic cell lines: Melanoma, Prostate, Breast, Kaposi sacrcoma and B16-Lymphoma cancer cell lines. Methodology/Experimentation: The bioactive compounds from Ball Moss were first extracted, isolated and identified. The fresh plant material was collected from power lines in Jamaica after which it was thorough washed, dried in a steam oven at 70°C, then milled and extracted with methanol (MeOH). Isolation of the bioactive compounds was done in two phases. Firstly, isolates from the crude extract was isolated by column chromatography and sub-fractions processed by bio-guided fractionation. During phase two, advanced separation technologies, including HPLC, supercritical fluid chromatography and capillary electrophoresis, were used followed by LC/MS and finally NMR. The bioassays of the isolated fractions were tested against the five different histogenic cancer cell lines in vitro using trypan blue exclusion and 3H Thymidine incorporation assays. The in vivo studies included 10 nude mice per group and using the crude form of the extract at 10mg per mice per day for 7 days. The extracts were tested in vivo against the same tumor cell lines and compared to controls administered normal saline treatment. Results: Utilizing the bioassay-guided fractionation process, the bioactive moiety was isolated at 98% purity. This purified compound tested in vitro demonstrated to be highly effective at a rate of in excess of 95% cell kill in the 5 different histogenic cell lines. The in vivo studies were equally impressive utilizing the crude extract. All 5 different tumors responded to the treatment by reducing the tumor size from 0.4mm X 0.4mm to almost non-existent on gross examinations of tumor cell lines (see images below). While the histological assessment using immuno-histochemical staining revealed that 90 to 95% of the tumors had undergone cell death cell which was due to apoptosis. There were no observations in the animals of any indications of any toxicity in the in vivo studies. The representative sample of gross tumors from a xenograft of the growth of Kaposi Sarcoma in nude mice and the histological results showing extensive necrosis following the use of Ball Moss extract and the immune-histochemistry, demonstrated cell death by apoptosis. It is to be noted that the treatments of all 5 cancer cell demonstrated the same level of bioactivity. Discussion/Conclusion: The findings from this study strongly indicate that these newly extracted compounds have significant anti-cancer / anti-HIV properties. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5266. doi:1538-7445.AM2012-5266

Of mice and men: a comparative study of cancer-associated fibroblasts in mammary carcinoma

Introduction.The initial clinical experience from targeted therapy for breast cancer has been mixed. While important progress has been made in the care of a subset of patients characterized by amplification of HER2 through the use of trastuzumab, other targeted therapies have failed to improve the outcome for large, unselected groups of patients. Thus, efforts to find prognostic or predictive biomarkers to enable tailored therapy are highly warranted. Genetically engineered mouse models of human cancer provide a convenient setting in which to perform explorative studies. However, there is a paucity of comparative studies between mouse and human tumours in order to validate the use of mouse models as discovery tools.Materials and methods.Here, we have compared the localization of markers for cancer-associated fibroblasts in the MMTV-PyMT mouse model of mammary carcinoma with that of human breast cancer. The expression of α-smooth muscle actin, platelet-derived growth factor receptor-α, and fibroblast-specific protein-1 was assessed by immunostaining of sections from tumours of MMTV-PyMT mice. Information about the distribution of the same markers in human breast cancer was derived from the publicly available database the Human Protein Atlas.Results.Both mouse and human mammary carcinomas were infused by a rich fibrotic stroma. While no marker was capable of identifying all stromal fibroblasts, the expression pattern of each marker was remarkably similar in mouse and human.Discussion.We conclude that the MMTV-PyMT mouse model of breast cancer will have utility as a discovery tool for biomarkers of cancer-associated fibroblasts during malignant conversion.

Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models

Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinical testing is a challenge that has not yet been met although tremendous advances have been made. A combined approach of cell culture and mouse models of human cancer is most likely to predict the efficacy of novel anti-cancer treatments in human clinical trials.

Swainsonine Activates Mitochondria-mediated Apoptotic Pathway in Human Lung Cancer A549 Cells and Retards the Growth of Lung Cancer Xenografts

Swainsonine (1, 2, 8-trihyroxyindolizidine, SW), a natural alkaloid, has been reported to exhibit anti-cancer activity on several mouse models of human cancer and human cancers in vivo. However, the mechanisms of SW-mediated tumor regression are not clear. In this study, we investigated the effects of SW on several human lung cancer cell lines in vitro. The results showed that SW significantly inhibited these cells growth through induction of apoptosis in different extent in vitro. Further studies showed that SW treatment up-regulated Bax, down-regulated Bcl-2 expression, promoted Bax translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, which in turn caused the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), resulting in A549 cell apoptosis. However, the expression of Fas, Fas ligand (FasL) or caspase-8 activity did not appear significant changes in the process of SW-induced apoptosis. Moreover, SW treatment inhibited Bcl-2 expression, promoted Bax translocation, cytochrome c release and caspase-3 activity in xenograft tumor cells, resulting in a significant decrease of tumor volume and tumor weight in the SW-treated xenograft mice groups in comparison to the control group. Taken together, this study demonstrated for the first time that SW inhibited A549 cancer cells growth through a mitochondria-mediated, caspase-dependent apoptotic pathway in vitro and in vivo.

Methoxyethylamino-numonafide Is an Efficacious and Minimally Toxic Amonafide Derivative in Murine Models of Human Cancer

Amonafide is a DNA intercalator in clinical development for the treatment of cancer. The drug has a 5-position amine that is variably acetylated to form a toxic metabolite in humans, increasing adverse effects and complicating the dosing of amonafide. Numonafides, 6-amino derivatives of amonafide that avoid the toxic acetylation, also show in vitro anticancer activity, as we have previously described. Here, we report the in vitro and in vivo activities of two numonafides, 6-methoxyethylamino-numonafide (MEAN) and 6-amino-numonafide (AN) with comparisons to amonafide. The in vitro potencies and cellular anticancer mechanisms are similar for the two numonafides and amonafide. Results from several mouse models of human cancer demonstrate that AN and MEAN require slightly higher doses than amonafide for equal efficacy in short-term dosing models, but the same dose of all three compounds in long-term dosing models are equally efficacious. MEAN is tolerated much better than amonafide and AN at equally efficacious doses based on weight change, activity, stool consistency, and dose tolerance with survival as the end point. The studies presented here demonstrate that MEAN is much less toxic than amonafide or AN in mouse models of human liver and gastric cancers while being equally efficacious in vivo and inhibiting cancer cells through similar mechanisms. These findings demonstrate that numonafides can be less toxic than amonafide and support further preclinical development and novel anticancer agents or as replacements or amonafide.

Abstract 668: Second generation silicon derivatives of indomethacin: Synthesis of potent COX-2 selective agents with improved anticancer activity

Abstract Elevated tumor cyclooxygenase-2 is associated with poor overall survival in patients with a variety of cancers. Patients with elevated COX-2 that receive a COX-2 inhibitor have demonstrated improved survival. Indomethacin (IM) is a COX-non-selective inhibitor with demonstrated anticancer activity in patients. The anticancer effects of IM are related to inhibition of COX-2 as well as COX-independent targets. We now report the improved synthesis and activity of IM-sila- amide derivatives where strategic silicon addition results in COX-2 selective IM derivatives that demonstrate activity in mouse models of human cancers and are devoid of the COX-1 associated toxicities. The sila-IM compounds demonstrated improved inhibition of purified human COX-2, IC50 0.2 uM and limited inhibition of COX-1 up to 10 uM. Sila-IM derivatives were also found to be potent inhibitors of NF-κB transcription activating function at concentrations below 1.0 UM. A sila-IM derivative Silexsyn was tested in various animal models of human cancer following oral administration. Significant activity was observed in models of non-small cell lung cancer and pancreas cancer. Potent synergism was observed for Silexsyn in combination with EGFR inhibitors. A synthetic methodology incorporating a heteroatom in the amino-functional silane has been developed and used to generate second-generation sila-IM derivatives that could have improved pharmacological properties. The introduction of silicon into an approved scaffold represents an efficient strategy for the rapid production of biologically relevant therapeutics for the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 668. doi:10.1158/1538-7445.AM2011-668

Abstract 767: Gypsophila saponins significantly augment the cytotoxicity of saporin-based anti-CD19, -CD22, -CD38 and -CD71 immunotoxins in human leukemia and lymphoma

Abstract Expanding the therapeutic window of immunotoxins (IT) is an important goal that would open up greater therapeutic possibilities for this class of drug. Saponins from Gypsophila paniculata have been shown to augment the cytotoxicity of the ribosome-inactivating protein (RIP) saporin and saporin containing cytotoxins that are directed against EGFR in cell culture and mouse models of human cancer. The mechanism through which saponins exert this effect is not clearly understood but is probably mediated through membrane disruption of endosomes that contain internalised IT thus allowing more efficient escape of IT to the cytosol and thence direct access of the RIP to target ribosomes. Here we show that Gypsophila saponins (SA) dramatically and significantly augment the cytotoxicity of saporin-based ITs directed against CD19, CD22, CD38 and CD71 expressed on the membrane surface of five different human leukaemia and lymphoma cell lines. We observed a high degree of variability in the augmentive effect exerted by SA, not only between different cell lines but also between different target molecules expressed on the same or on different cell lines. For instance SA augmented the anti-CD19 IT BU12-Saporin by only 10-fold in NALM-6 cells (representing a reduction in IT IC50 from 3 × 10−10M to 3 × 10−11M by SA) but by a massive 9.43 million-fold in Daudi cells (representing a reduction in IT IC50 from 5 × 10−9M to 5.3 × 10−16M by SA), despite there being a similar expression level of CD19 by each cell line. Through antibody blocking experiments and the use of cells not expressing the antigen targeted by the IT under study we revealed that SA does bring about a modest reduction in the immunospecificity of IT activity. However, by scheduling pulse exposure of target cells to IT first followed by washout and then exposure to SA it was possible to retain full immunospecificity. We speculate that the differences in SA augmentive effect on IT cytotoxicity between different cell lines and different target molecules on the same cell line probably represents individual variations in lipid/cholesterol membrane composition, particularly within lipid microdomains (lipid rafts) to which target molecules such as CD19 and CD38 migrate prior to receptor-mediated endocytosis following cross linking by the antibody component of IT. The variations in augmentive effect of SA on IT cytotoxicity observed for the different cell lines in the present study makes understanding the mechanism behind this phenomenon very important if saponins are to be sucessfully developed as a treatment modality to be used in conjunction with saporin-based ITs or cytotoxins for individual patients with haematological and other types of malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 767. doi:10.1158/1538-7445.AM2011-767

The Mouse Tumor Biology Database (MTB)

The Mouse Tumor Biology Database (MTB) is designed to provide an electronic data storage, search, and analysis system for information on mouse models of human cancer. The MTB includes data on tumor frequency and latency, strain, germ line, and somatic genetics, pathologic notations, and photomicrographs. The MTB collects data from the primary literature, other public databases, and direct submissions from the scientific community. The MTB is a community resource that provides integrated access to mouse tumor data from different scientific research areas and facilitates integration of molecular, genetic, and pathologic data. Current status of MTB, search capabilities, data types, and future enhancements are described in this article.

How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review.