Murine Models to Evaluate Novel and Conventional Therapeutic Strategies for Cancer

Abstract

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

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…The outcomes of preclinical mouse studies form the basis for understanding disease biology, immune and therapeutic responses, and determining which therapies to take into clinical trials [80][81][82][83]. Many authors have asserted that a major problem in research is irreproducibility [80,81,84,85].…”

The use of the orthotopic model to validate antivascular therapies for cancer

“…Studies have established that the expression of cellular properties required for acquiring both the primary and the metastatic (the ability to metastatize to and colonize the distant organs) phenotypes, are dependent on both intrinsic properties of the tumour cells and host factors, which can differ between tissues and organs (Talmadge, 2007).…”

“…Animal models, by definition, are an approximation of reality, and their use for studying and developing antivascular therapies is controversial (Talmadge, 2007).…”

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenograft model of gastric cancer using two-photon laser scanning microscopy

“…Our method needs to be improved. There is a site-specific variation in response to chemotherapy for a number of human malignant tumors [33]. We believe that metastatic xenografts are more practical than subcutaneous xenografts for evaluating the efficacy of novel anti-cancer chemotherapeutic agents.…”