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Natural products from plants, fungi, and microbes continue to serve as valuable leads in anticancer drug discovery. While many exhibit potent in vitro activity, few demonstrate comparable efficacy in vivo. From 1981 to 2014, 22% of the 174 cancer drugs approved by the FDA and similar agencies were natural products, 14% were synthetic analogs, and 10% were unmodified natural compounds [1]. However, promising in vitro findings often fail to translate clinically due to challenges such as metabolism and limited bioavailability. In vivo testing is thus essential to evaluate therapeutic potential before progressing to clinical trials.
Animal models are essential in early-stage drug research to evaluate pharmacokinetics (absorption, distribution, metabolism, and elimination), safety, and efficacy. They are broadly classified into homologous models (closely replicate human disease), isomorphic models (share similar symptoms but differ in etiology), and predictive models (forecast treatment responses) [2]. Model selection must be carefully aligned with the research objective, considering ethical viability, species relevance, similarity to the human cancer type, and experimental complexity. Practical factors such as genetic background, immune status, cost, infrastructure, and study duration also influence the choice of an appropriate model.
Various animal species have been employed in in vivo tumor studies, including mice, rats, zebrafish, pigs, goats, dogs, and rabbits [3]. Among these, murine models, particularly mice, are the most extensively utilized, accounting for approximately 95% of cancer research studies [4]. Depending on the experimental objectives, researchers may choose between immunocompetent mice (with intact immune systems) and immunodeficient mice (lacking key immune components).
Several types of in vivo models are used to investigate tumor development and evaluate therapeutic efficacy:
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Spontaneous tumor models - tumors arise naturally, reflecting human cancer heterogeneity but with limited control. |
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Induced tumor models - using carcinogens to replicate environmental and mutational drivers of cancer, though often time- and resource-intensive. |
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Transplantable tumor models - involving tumor cell implantation using heterotopic, orthotopic, or xenografts that offer high reproducibility, particularly xenografts for studying human tumors in immunocompromised mice. |
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Genetically engineered mouse models (GEMMs) - recapitulate specific oncogenic mutations, offering mechanistic insights in a native microenvironment. |
To ensure reliable and interpretable outcomes, a robust experimental design is paramount. This involves establishing well-defined control and treatment groups, adhering to ethical guidelines, and applying standardized protocols for data collection and analysis. Researchers are also ethically obligated to follow the principles of the 3Rs: Replacement (using alternatives to animal models where feasible), Reduction (minimizing the number of animals used), and Refinement (optimizing procedures to reduce pain and distress).
Ultimately, in vivo models remain indispensable for evaluating the anticancer potential of natural compounds. They serve as a bridge between laboratory discoveries and clinical application, enabling researchers to refine hypotheses, identify the most promising therapeutic candidates, and advance the development of safer and more effective cancer treatments. While no single model can fully replicate human disease, ongoing technological advancements continue to improve their predictive accuracy, bringing us closer to better outcomes for cancer patients.
References
Date of Input: 18/08/2025 | Updated: 25/08/2025 | azah
Director
Institute of Bioscience,
Universiti Putra Malaysia,
Email inquiry about laboratory services: ibs_services@upm.edu.my
