4.9.5 Oncology Models
Cancer pharmacology models range from chemically induced carcinogenesis models, which recapitulate the multistep process of tumourigenesis over an extended...
Cancer pharmacology models range from chemically induced carcinogenesis models, which recapitulate the multistep process of tumourigenesis over an extended time course, to transplantable tumour (xenograft) models, which provide a rapid, reproducible platform for evaluating candidate anticancer agents against an established tumour.
Chemical Carcinogenesis — DMBA-Induced Model
Chemically induced carcinogenesis models use a defined carcinogenic initiator, most commonly 7,12-dimethylbenz[a]anthracene (DMBA), to induce tumour formation in a specific target organ, allowing study of the complete multistep carcinogenic process from initiation through promotion to malignant progression. In the widely used DMBA-induced mammary carcinogenesis model, a single or repeated oral or subcutaneous dose of DMBA is administered to young female Sprague-Dawley rats during a defined window of mammary gland susceptibility, producing palpable mammary tumours within eight to sixteen weeks that share substantial histopathological and hormone-responsiveness similarity with human breast cancer. Tumour incidence, latency, multiplicity, and volume (calculated from calliper measurements) are the principal endpoints, alongside terminal histopathological grading. Tamoxifen and cytotoxic chemotherapeutic agents serve as reference comparators depending on the mechanism under investigation. The model's key strength is its recapitulation of the full multistep carcinogenic process, including tumour-microenvironment and immune-system interactions absent from transplantable models; its principal limitation is the extended study duration and the ethical and practical burden of a full carcinogenesis study.
Transplantable Tumour — Xenograft Model
The xenograft model provides a considerably faster and more standardised platform for anticancer drug screening by implanting human tumour cells (subcutaneously, for accessible measurement, or orthotopically, at the tissue site of tumour origin, for greater biological relevance) into immunodeficient mice — commonly athymic nude mice or, for enhanced human cell engraftment, NOD-SCID or NSG strains lacking functional T, B, and natural killer cell populations. Tumour growth is monitored longitudinally by external calliper measurement (for subcutaneous tumours) or bioluminescence/fluorescence imaging (for orthotopic or metastatic tumours engineered to express a reporter gene), with tumour volume, growth-delay relative to vehicle control, and, in longer studies, overall survival serving as principal endpoints. Standard-of-care chemotherapeutic agents relevant to the specific tumour type under study serve as reference comparators. The xenograft model's chief advantage is speed and reproducibility, and its use of genuine human tumour tissue; its chief limitation is the immunodeficient host, which precludes any assessment of immune-mediated antitumour mechanisms — an increasingly important limitation given the centrality of immunotherapy to contemporary oncology, addressed by the newer syngeneic and humanised-mouse tumour model platforms.