Insights into cancer from transgenic mouse models

Macleod, Kay F.; Jacks, Tyler

doi:10.1002/(sici)1096-9896(199901)187:1<43::aid-path246>3.0.co;2-p

Cited by 121 publications

(49 citation statements)

References 212 publications

(326 reference statements)

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“…Overall, GEMs have seldom been used to test novel anti-cancer therapeutics with the goal of accurately predicting clinical responses. 69,70 The few studies that have compared GEMs using clinically effective agents have not been encouraging. 66,[71][72][73] Thus, despite their mechanistic promise, transgenic mouse models have not yet demonstrated a role in drug discovery.…”

Section: Gemsmentioning

confidence: 99%

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

Talmadge

Singh

Fidler

et al. 2007

The American Journal of Pathology

411

330

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Animal models, by definition, are an approximation of reality, and their use in developing anti-cancer drugs is controversial. Positive retrospective clinical correlations have been identified with several animal models, in addition to limitations and a need for improvement. Model inadequacies include experimental designs that do not incorporate biological concepts, drug pharmacology, or toxicity. Ascites models have been found to identify drugs active against rapidly dividing tumors; however, neither ascitic nor transplantable subcutaneous tumors are predictive of activity for solid tumors. In contrast, primary human tumor xenografts have identified responsive tumor histiotypes if relevant pharmacodynamic and toxicological parameters were considered. Murine toxicology studies are also fundamental because they identify safe starting doses for phase I protocols. We recommend that future studies incorporate orthotopic and spontaneous metastasis models (syngeneic and xenogenic) because they incorporate microenvironmental interactions, in addition to confirmatory autochthonous models and/or genetically engineered models, for molecular therapeutics. Collectively, murine models are critical in drug development, but require a rational and hierarchical approach beginning with toxicology and pharmacology studies, progressing to human primary tumors to identify therapeutic targets and models of metastatic disease from resected orthotopic, primary tumors to compare drugs using rigorous, clinically relevant outcome parameters. Animal models are critical for the development of novel therapeutics; however, we have been minimally successful in decreasing the age-adjusted death rate for cancer compared with cardiac disease. In 2003, for the first time since 1930 when epidemiological records were initiated, fewer people (Ͻ85 years old) died of cardiac disease as compared with cancer.1 This historic change was attributable to a 60, 70, and 0% decrease in mortality by heart disease, stroke, and cancer, respectively. Thus, it is warranted to review the approaches and tumor models used in the identification and development of new anti-cancer therapeutics. Tumor initiation, progression, and metastasis is a complex, multifactorial process that selects tumor variants from a heterogeneous primary tumor.2,3 Therapeutic intervention is also a selective pressure that can result in tumor cell populations refractory to specific drugs.4 Therefore, to model and study tumor biology and drug activity, the selection of clinically relevant animal and tumor models is critical.Originally, drug screens used leukemic cell lines that, when injected intraperitoneally (i.p.) resulted in tumor ascites. These tumor models were successful in identifying active therapeutics against leukemias and some lymphomas; however, they were inadequate for the identification of therapeutics against solid tumors. 5-7

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Section: Gemsmentioning

confidence: 99%

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

Talmadge

Singh

Fidler

et al. 2007

The American Journal of Pathology

411

330

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“…To more effectively model human disease, mutant and transgenic (Tg) lines of mice that spontaneously develop malignancies have been developed (63)(64)(65). In these mouse models, key targets in oncogenesis can be evaluated, and can include the study of initial or early events in the disease processes.…”

Section: Spontaneous Tumor Modelsmentioning

confidence: 99%

It's not just about anatomy: In vivo bioluminescence imaging as an eyepiece into biology

Contag

Ross

2002

Magnetic Resonance Imaging

254

189

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Among the newly described tools that enable analyses of cellular and molecular events in living animals, in vivo bioluminescence imaging (BLI) offers important opportunities for investigating a wide variety of disease processes. BLI utilizes luciferase as an internal biological light source that can be genetically programmed to noninvasively "report" the presence or activation of specific biological events. Applications of BLI have included the use of luciferase to demonstrate expression of cell-and tissue-specific promoters, label cell populations, guide detection by other imaging modalities, and detect protein-protein interaction. These applications of BLI technology have allowed quantitative measurements of tumor burden and treatment response, immune cell trafficking, and detection of gene transfer. Spatiotemporal information can be rapidly obtained in the context of whole biological systems in vivo, which can accelerate the development of experimental therapeutic strategies. This paper provides a review of the biological applications in which in vivo BLI has been utilized to nondestructively monitor biological processes in intact small animal models, and highlights some of the advancements that will increase the versatility of BLI as a molecular imaging tool.

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“…M olecular investigations of the functions of oncogenes and tumor suppressor genes have been facilitated by analysis of mouse models (1,2). With respect to prostate carcinogenesis, mouse models potentially can overcome inherent difficulties in studying the molecular genetics of this disease in humans (3)(4)(5).…”

mentioning

confidence: 99%

Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis

Kim

Cardiff

Desai

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

293

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Insights into cancer from transgenic mouse models

Cited by 121 publications

References 212 publications

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

It's not just about anatomy: In vivo bioluminescence imaging as an eyepiece into biology

Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis

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