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178]

Review Article
Use of rodents as models of human diseases
Thierry F. Vandamme

University of Strasbourg, ABSTRACT

Faculty of Pharmacy, UMR
Advances in molecular biology have significantly increased the understanding of the biology of different
7199 CNRS, Laboratory of
Concept and Application
diseases. However, these discoveries have not yet been fully translated into improved treatments for patients
of Bioactive Molecules, with diseases such as cancers. One of the factors limiting the translation of knowledge from preclinical studies
Biogalenic Team, 74 to the clinic has been the limitations of in vivo diseases models. In this brief review, we will discuss the
Route du Rhin, 67400 advantages and disadvantages of rodent models that have been developed to simulate human pathologies,
Illkirch Graffenstaden, focusing in models that employ xenografts and genetic modification. Within the framework of genetically
France engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases
in the mouse and the preclinical studies that have already been undertaken. We will also discuss how recent
Address for correspondence:
improvements in imaging technologies may increase the information derived from using these GEMs during
Dr. Thierry F. Vandamme,
E‑mail: vandamme@unistra.fr early assessments of potential therapeutic pathways. Furthermore, it is interesting to note that one of the
values of using a mouse model is the very rapid turnover rate of the animal, going through the process of birth
to death in a very short timeframe relative to that of larger mammalian species.
Received : 20‑11‑13
Review completed : 20‑11‑13
Accepted : 20‑11‑13 KEY WORDS: Cancer, genetically modified animals, human diseases, rodents, transgenic

A nimal experiments remain essential to understand

the fundamental mechanisms underlying the onset of
malignancies and to discover improved methods to prevent,
toxicological assessments and to support human drug approvals.
Humane considerations are emphasized in an effort to minimize
adverse effects. Nevertheless, since we cannot replace all animal
diagnose and treat diseases. The current excellence of animal experiments in the immediate future, the highest standards of
care standards are consistent with the experimental conditions welfare are upheld.[1]
needed when conducting cancer research.[1]
In terms of oncology drug products, the preclinical studies
For scientists to understand how diseases develop and spread were previously limited to the transplantation of murine or
throughout the body and to discover new and more effective human cancers into mice. Most recently, some investigators
ways to diagnose and treat these diseases, it is necessary to have explored alternatives to these transplantation models,
conduct live animal research. Although animal studies (over 95% such as the study of animals that naturally develop cancers
of which are conducted in mice) are essential for gaining the which are similar to that in humans. An example of this is seen
necessary understanding of complex disease processes, they in the parallel assessments underway for canine and human
should be performed only after exhausting information that osteosarcoma.[2] Alternatively, animals can be genetically
can be derived from other tools such as disease cell lines. engineered to develop cancers with features relevant to the
Furthermore, animal studies are also required by regulatory human disease.[3] Experiments with these animals produce
authorities before any trials of new drugs can be tested in valuable information about the role of specific genes in
humans. Indeed, preclinical animal studies are required for biological processes and diseases.

The first transgenic mouse was created in 1974 at the

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Massachusetts Institute of Technology. It was created through
Quick Response Code: an in vitro micro‑injection of Simian virus 40 into mouse
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blastocysts and early embryonic infection with retrovirus. The
technology to create transgenic animals broke new ground in
the scientific community and enabled scientists to seek new
DOI:
ways of treating diseases and developing new drugs. The ability
10.4103/0975-7406.124301
to introduce new genetic information into the germ line of

How to cite this article: Vandamme TF. Use of rodents as models of human diseases. J Pharm Bioall Sci 2014;6:2-9.

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Vandamme: Use of rodents as models of human diseases

complex organisms has completely changed and enhanced the A large variety of human and murine cell lines derived from
study of all aspects of biologic processes. Transgenic mouse both, solid tumors or leukemias, covering a wide range of tumor
models in toxicology have primarily been used to screen geno‑and phenotypes, have been adapted to grow in a murine
drugs for carcinogenicity and to understand the mechanisms host and thus allow testing of a compound in the appropriate
of toxicity. These mouse models can reliably predict the tumor model [Table 1].
carcinogenic potential of compounds and significantly reduce
the risk of using these drugs in clinics to treat human diseases. The earliest xenograft models in which human tumor cells
were grown in immunosuppressed mice involved subcutaneous
Use of short‑term experiments on transgenic mice in implantation of human cell lines. Subcutaneous xenograft
combination with 2‑year chronic studies on rats could models have been popular because they are easy to establish,
increase the overall accuracy of detecting carcinogens and easy to manage and lend themselves to ready quantitation of
non‑carcinogens. Testing new drugs using different species also the tumor burden. More recently, orthotopic xenograft models,
reduces false results. Additional advantages of using transgenic in which the tumor cells are implanted in the tumor site of
assays include reduced duration of studies, conservative use of origin, have been used with greater frequency in animal studies
animals and lower cost relative to a traditional 2‑year rodent of cancers. Orthotopic xenograft models are advantageous for
chronic toxicity study (http://www.ruro.com/blog/3752, viewed their ability to mimic local tumor growth and recapitulate the
27th January 2013). pathways of metastasis seen in human cancers. In addition,
recent innovations in cell labeling techniques and small‑animal
Xenografts imaging have enabled investigators to monitor the metastatic
process and quantitate the growth and spread of orthotopically
Xenografts (xenos‑from the Greek meaning “foreign”), is a graft implanted tumors.[36]
obtained from a member of one species and transplanted to a
member of another species, genus, or family. The transplantation Progress in oncology drug development has been hampered by
can consist of living cells, tissues or organs from one species to a lack of preclinical models that reliably predict clinical activity
another. Xenografts are used to answer key questions in the of novel compounds in cancer patients. In an effort to address
field of cancer research when it is necessary to rely upon the these shortcomings, there has been a recent increase in the
use of animal model systems that closely resemble tumor use of patient‑derived tumor xenografts (PDTX), engrafted
progression in the human patient. Human xenografts growing into immune‑compromised rodents such as athymic nude or
in immunodeficient mice are a well‑established and useful non‑obese diabetic/SCID mice, for use as preclinical models.
model for studying human tumor biology in a system that better
mimics the primary tumor as compared to cells grown in vitro.
Often times, xenograft studies use highly passaged cell lines that Table 1: Subcutaneous in vivo tumor cell lines models
have been genetically modified and artificially cultured, leading Tumor origin Tumor cell lines Species References
to a clonal selection that may not be observed in patients. Ideal Blood/leukemia MV4‑11 Human [6]

primary tumor tissue xenografts result from patient‑derived MOLM‑13 Human [7]

explants, established as models, at low passage numbers (<10 HL‑60 Human [8]

passes removed from patient). Furthermore, these cell lines Bone SJSA‑1 Human [9]

Brain C6 Rat [10]

are not grown in plastic or propagated as cell cultures. [4,5] Breast MDA‑MB‑231 Human [11]

Establishing xenograft tumor models from patient‑derived MCF7 Human [12]

tumor tissue at low passage is believed to conserve original Cervix C33A Human [13]

tumor characteristics such as heterogeneous histology, clinical HeLa Human [14]

biomolecular signature, malignant phenotypes and genotypes, Colon HCT‑116 Human [15]

HT29 Human [16]

tumor architecture and tumor vasculature. Based on this SW620 Human [17]

prevalent hypothesis, primary tumor xenografts are believed to CT26 Mouse [18]

offer relevant predictive insights into clinical outcomes when LS 174T Human [19]

evaluating the efficacy of novel cancer therapies. LoVo Human [20]

Colo‑205 Human [21]

Gastric MKN‑45 Human [22]

Subcutaneous xenograft models are the standard technique for
TMK‑1 Human [23]
determining the efficacy of new cancer agents in vivo and the Kidney RENCA Mouse [24]

most commonly performed. It is also the fastest and lowest cost Lung H460 Human [25]

model. In these subcutaneous models, the tumor is grown under A549 Human [26]

the skin of a nude or severe combined immunodeficiency (SCID) Calu‑6 Human [27]

Ovary SKOV‑3 Human [28]

mouse and the tumor growth is monitored by measuring the size
Pancreas MiA‑PaCa2 Human [29]
of the tumor with calipers. In xenograft studies, cultured cells AsPC1 Human [30]

are generally injected subcutaneously into immunodeficient Prostate PC‑3 Human [31]

mice, which are then treated with the compound of interest LNCaP Human [32]

for 2‑6 weeks during which time subcutaneous tumors develop. Skin A431 Human [33]

The study is “positive” if the compound of interest reduces the A375 Human [34]

B16‑F10 Mouse [35]

rate of growth of new tumors.

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Vandamme: Use of rodents as models of human diseases

Numerous tumor‑specific PDTX models have been established of efficient and targeted treatments (e.g., leukemia,
and importantly, they are biologically stable when passaged in hypertension and obesity).
mice in terms of global gene‑expression patterns, mutational
status, metastatic potential, drug responsiveness and tumor The major applications for genetically modified animals in
architecture. These characteristics might provide significant agriculture are
improvements over standard cell‑line xenograft models.[5] • To generate animal with desired breeding traits (e.g., lower
phosphorous in the dung).
Genetically Engineered Animal Models • To induce resistance against disease (e.g., fish farming) (Basel
Declaration, 2010).
Because the genetics and histology of xenografts do not
recapitulate the genetics and histology of human tumors, One of the goals in using transgenic animals is that it allows for
genetically engineered animal models were developed. a reduction in the use of larger animals. The use of GEMs also
provides an opportunity to improve our understanding of the
The use of genetically modified mice for carcinogenicity mechanisms of action for potential therapeutic compounds. At
evaluation began more than 20 years ago, when researchers present, the European Commission consider that mice appear
found that different strains of genetically engineered mice to be the most common genetically engineered animal models
demonstrated that cancer incidence is increased and tumor to study new drug compounds for different diseases for the
latency is decreased in mice whose germ line, the Ha‑ras following reasons[42]
oncogene, has been inserted. Previously, the selection of mouse • The mouse is the most common model organism for
oncology models was based simply on availability of a mouse preclinical studies even though it has not proven particularly
strain and a known compatible tumor. This frequently resulted reliable at predicting the outcome of studies in humans.
in the use of tumor models that while long on history were short • Mice have many advantages over other model organisms:
on homology and quality control. For these reasons, preclinical Their genome is similar to the human genome (99%), a good
efficacy testing for anti‑tumor therapies should progress through genetic/molecular toolbox is available and the animal’s small
a series of models of increasing sophistication that includes size facilitates large scale/high throughput studies making it
incorporation of genetically engineered animals and orthotopic a cost‑efficient model. Therefore, it’s potential for making
and combination therapy models. medical research and in particular drug development more
efficient could be increased by solving a range of identified
Genetically modified animals are organisms in which specific bottlenecks.
genes have been altered (added or ablated) to create models for • Mouse models have been successfully used to validate
human and animal diseases. A transgenic animal is defined as drug targets and to determine efficacious and safe dosage
an animal that carries one or more foreign genes, deliberately schemes for combination treatments in humans. These
introduced through insertion into the animal’s genome. The cases have one factor in common: They do not aim to fully
foreign gene is constructed using recombinant deoxyribonucleic model a disease or disease mechanisms, but rather set out
acid (DNA) technologies. The introduction of a gene can also to obtain specific functional information.
generate therapeutic medicinal products. Standard genetically • Genetically modified mice need to be validated, reproducible,
modified animals include laboratory flies, fish, worms, rodents robust and cost‑effective to be considered optimal by the
and (for agricultural or production purposes) pigs, sheep and pharmaceutical industry.
cows. In no case is genetic modification of man implied.[37,38] • Transgenic humanized mice could provide good preclinical
screening and safety testing models for use in lead
In a modern GEM models, oncogenes are activated and/or identification and optimization.
tumor‑suppressor genes (TSGs) are inactivated somatically, • The large‑scale phenotyping of genetically engineered mice
generally through temporally controlled and tissue‑specific can provide valuable information on gene function which
expression of CRE recombinase (tyrosine recombinase is relevant for human health and disease.
enzyme derived from the P1 Bacteriophage). Animals then • The use of mice in clinical studies has proven effective
develop tumors in the tissue of interest (in this case the lung). in a number of cases. Dosage regimes of new treatments
Tumor‑bearing genetically engineered mice are then treated with or treatment combinations can rapidly be optimized by
the compound of interest and serially assessed for response.[39] co‑clinical trials with mice, allowing fast application in
humans with greater patient safety. This provides increasing
The benefits of engineered animal models are numerous. opportunities in particular for the rapid development of
Examples include[40,41] treatments for very rare diseases where low patient numbers
• Development and testing of safe and effective products for otherwise hamper the creation of clinical trials.
human application (e.g., human antibodies).
• The production of recombinant products (anti‑coagulant; One of the key bottlenecks that needs to be solved concerns
therapeutic antibodies). the aggressive patenting strategy (including the patenting of
• A means to study disease mechanisms in a complex mouse genes and broad based methods patents) and overly
organism (diabetes). restrictive licensing terms in material transfer agreements, which
• Understanding the mechanistic causes and pathways hamper the construction, sharing, use and proper exploitation of
underlying human disease, to permit the development mouse models. Representatives from the European Medicines

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Vandamme: Use of rodents as models of human diseases

Agency and the Food and Drug Administration confirmed that and bioluminescence imaging. These new technologies will
data stemming from mouse models will be taken into account hopefully support the use of GEMs in preclinical trials and help
wherever the relevance has been clearly proven within the given determine if trials in GEMs are more predicative than xenografts
context. of human responses.[43]

The efficient development and use of these mouse models The selection of murine cancer models is often based simply on
necessitates the collaboration of experts within academia, the availability of a mouse strain and on a known compatible
clinicians and industry. In this regard, there is a need for tumor. Frequently this information results in use of tumor
specialist training programs that provide venue whereby insights models long on history, but short on homology and quality
can be shared from mouse pathologists, human pathologists control. Other factors need to be considered, including
and clinicians in order to better define the opportunities and genetics, sex, immunological status, method and site of tumor
limitations associated with use of these mouse models. implantation, technical competence and biological activity
of the tumor, protocol sequence and timing and selection of
The Use of Mouse Models to Support Therapeutic endpoints. Each of these variables can influence the data derived
Drug Development from use of these tumor models.

Animal models are being increasingly used in the study of disease It is frequently observed that murine tumor models error
progression and for safety assessments of new compounds. They towards false positive therapeutic results, curing the cancer in
are a powerful tool for developing a more detailed understanding mice but not in humans. This perceived inadequacy of classical
of the role specific genes play in biological pathways. At the transplantation models for the development of anti‑tumor
present time, the ability to introduce new genetic information therapies is currently a pivotal factor in driving the development
into the germ line of complex organisms has completely changed and use of GEMs. The underlying limitations of tumor
and enhanced the study of all aspects of biologic processes. models also serve to reinforce the need for careful attention to
design (applying correct models to the question), conduct (using
Cancer multiple models) and interpretation (recognizing limitations
and applying stringent criteria to outcomes) of efficacy
Mouse models of human cancer are valuable tools for cancer studies for tumor modulation. Thus, while animal models
research. Although xenografts and GEMs possess limitations can provide a form of “high throughput” in the selection of
as well as advantages, each system plays a significant role in potential drug gable candidates, the use of these results to
preclinical testing. predict human clinical outcomes is premature. Therefore,
new strategies, techniques and continued improvements in
Tumor xenografts are easy to use, relatively inexpensive stringency and consistency of criteria used for evaluating
and reproducible. The main drawback of xenografts is that outcomes are necessary to ensure that tumor models in mice
the genetics and histology of the tumors are frequently not remain a useful tool for development of anticancer agents and
representative of the respective human tumor and thus far, devices.[44] Moreover, transitions from in vitro to preclinical and
these models have not been as predictive of therapeutic success then to clinical testing for tumor modulation remain difficult
as one would like.[43] The use of xenografts to design novel with a low rate of clinical entry for most therapeutic classes.
specific anti‑tumor therapies for enhanced and targeted drug Increased understanding of mechanisms of neoplasia through
delivery such as anti‑angiogenesis (inhibitors and enhanced macromolecular biology, genomics and bioinformatics is helping
permeation), immunotherapy (vaccines, monoclonal antibodies, to address treatment bottlenecks. These bottlenecks include a
toxin conjugates, prodrug activators, cytokine antagonists), lack of specificity, low efficacy, toxicity and drug resistance and
small molecules (inhibitors of growth, matrix and adhesion), the need to identify critical targets for clinical exploitation.
apoptosis (enhancers, inducers, proteasome inhibitors, reverse
DNA methylation), anti‑sense and gene therapy (TSGs) and The numerous studies evaluating new antitumor drugs use
cell cycle alterations (inhibitors) are not sufficient to support engineered animal models [Table 2].
their use as the sole drug screen in an anti‑tumor evaluation.
Therefore, to support the development of cancer therapeutics, Other applications
there needs to be a series of models used, including GEMs and
orthotopic and combination therapy models. Intestinal inflammation

In contrast to studies involving xenografts, GEMs are Rennick and Fort used interleukin (IL)‑10‑/‑mice, which
histologically and genetically accurate models of human spontaneously develop this pathological condition that
cancer but have disadvantages of heterogeneity with regard is characterized by discontinuous transmural lesions
to frequency, latency and growth. These disadvantages are affecting the small and large intestine. This inflammatory
reminiscent of the variable behavior of actual human tumors. response also includes the dysregulated production of
Recently, these shortcomings have been partly overcome with proinflammatory cytokines.[52] The uncontrolled generation of
the development of anatomic and molecular in vivo imaging interferon‑gamma‑producing CD41 T‑cells (Th1 type) has been
techniques such as magnetic resonance imaging (MRI) shown to play a causal role in the development of enterocolitis

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Table 2: Engineered animal models for anti‑tumor evaluations

Tumor origin Drug Engineered animal model References
Tumor‑induced angiogenesis Curcumin MPEG‑PCL micelles Transgenic zebrafish model [45]

HER2‑positive breast carcinomas Vitamin E analogs Breast tumor mouse model [46]

Prostate carcinoma Antigens TRAMP model [47]

Anti‑angiogenic activities Furanodiene Transgenic Tg (fli1: EGFP) zebrafish embryos [48]

Gastric tumor Cyclophosphamide CEA424‑SV40 large T antigen [49]

(CEA424‑SV40 TAg) transgenic mouse

Breast carcinomas CTCE‑9908 with docetaxel or DC101 Transgenic breast cancer mouse model [50]

(an anti‑VEGFR2 monoclonal antibody

Tumor angiogenesis siRNAs Transgenic mice developing HCC [51]

MPEG: Monomethoxy poly(ethylene glycol), PCL: Poly(ε‑caprolactone), EGFP: Enhanced green fluorescent protein, HER2: Human epidermal growth
factor receptor 2, TRAMP: Transgenic adenocarcinoma mouse prostate, VEGFR2: Vascular endothelial growth factor receptor 2, HCC: Hepatocellular
carcinoma

affecting these mutants. the study of IL‑102/2 mice have been unrelated to transamidase catalytic activity. Iismaa et al.[54] in
applied to an evaluation of the role of enteric organisms in their study reviewed recent insights into the physiology and
triggering intestinal disease, the mediators responsible for pathophysiology of TG family members that have come from
initiating and maintaining intestinal disease, the role IL‑10 studies of GEM models and/or inherited disorders. The review
plays in the generation and/or function of regulatory cells and focused on FXIII‑A, TG1, TG2, TG5 and protein 4.2, as mice
the results of IL‑10 therapy in experimental animal models deficient in TG3, TG4, TG6, or TG7 and they underlined the
of inflammatory bowel disease (IBD) and human patients necessity to use these engineered animals to study these proteins
with IBD. linked to human disease.

Hepatic steatosis and/or insulin resistance Nicotine addiction

Although rodent models do not always perfectly reproduce the Recently, Jean‑Pierre Changeux underlined the interest in using
human pathology of non‑alcoholic fatty liver disease (NAFLD), transgenic animals to study nicotine addiction and nicotinic
Postic and Girard concluded that the use of transgenic, receptors. Indeed, in an interesting review, he mentions that
knockout and knockdown mouse models have helped over recent studies in mice involving deletion and replacement of
the past years to better the understanding of the molecular nicotinic acetylcholine receptor subunits have begun to identify
determinants of NAFLD. Key enzymes of fatty acid synthesis, the molecular mechanisms underlying nicotine addiction and
such as acetyl‑CoA carboxylase, elongation of long‑chain fatty might offer new therapeutic strategies to treat this addiction.[55]
acids family member 6, stearoyl-Coenzyme A desaturase 1
(SCD1), glycerol‑3‑phosphate acyltransferase, or diacylglycerol Arachidonic acid metabolism and central nervous system
acyltransferase, have been shown, when knocked down, to pathology
reverse many of the metabolic defects associated with hepatic
steatosis and/or insulin resistance, indicating that decreased Bosetti used genetic mouse models to investigate the
TG synthesis in liver is a potential and interesting target for physiological and pathological roles of Arachidonic acid (AA)
the treatment of NAFLD.[53] Therefore, a better understanding release and metabolism in brain.[56] She concluded that although
of the function and/or regulation of the transcription factors data obtained in genetically altered mouse models should be
that control the activity of the enzymes modulating fatty interpreted with care because of possible compensatory changes,
acid synthesis in liver, namely carbohydrate response element knockout and transgenic mice provide a useful approach to
binding protein, sterol regulatory element binding protein‑1c identify the roles of specific enzymes of the AA cascade in
and liver X receptors, may in the future help the development physiological and pathological models. Therefore, these genetic
of potential therapeutic approaches for this disease animal models combined with the use of conditional knockouts,
in vivo ribonucleic acid interference and specific pharmacological
Patho‑physiology of transglutaminase inhibitors, may help to develop novel therapeutic strategies for
diseases involving altered brain AA metabolism.
The human TG family consists of a structural protein, protein
4.2, that lacks catalytic activity and eight zymogens/enzymes, AA is freed from a phospholipid molecule by the enzyme
designated factor XIII‑A (FXIII‑A) and TG1‑7, that catalyze phospholipase A2 (PLA2), which cleaves off the fatty acid,
three types of posttranslational modification reactions: but can also be generated from diacylglycerol by diacylglycerol
Transamidation, esterification and hydrolysis. These reactions lipase. AA is generated for signaling purposes appears to
are essential for biological processes such as blood coagulation, be derived by the action of a phosphatidylcholine‑specific
skin barrier formation and extracellular matrix assembly. cytosolic PLA2 (85 kDa), whereas inflammatory AA is
However, they can also contribute to the pathophysiology generated by the action of a low molecular‑weight secretory
of various inflammatory, autoimmune and degenerative PLA2 (14‑18 kDa). AA is a precursor in the production of
conditions. Some members of the TG family, for example, eicosanoids: (i) The enzymes cyclooxygenase and peroxidase
TG2, can participate in biological processes through actions lead to prostaglandin H2, which in turn is used to produce

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the prostaglandins, prostacyclin and thromboxanes; (ii) the therapeutics. Indeed, deficiencies in the standard preclinical
enzyme 5‑lipoxygenase leads to 5‑HPETE, which in turn methods for evaluating potential bioactive drugs, such as
is used to produce the leukotrienes; (iii) AA is also used in xenograft mouse models, have been highlighted as a key
the biosynthesis of anandamide; (iiii) some AA is converted obstacle in the translation of the major advances in basic
into hydroxyeicosatetraenoic acids and epoxyeicosatrienoic therapeutic research into meaningful clinical benefits. At
acids by epoxygenase. The production of these derivatives present, uses of xenograft mouse models for different drug
and their action in the body are collectively known as the developments appear to be limited. In contrast, opportunities
“AA cascade”. for applying GEM models more faithfully mimic biological
evolution of different human diseases. Greater use of such
Ovarian endometrioid adenocarcinoma GEMs for preclinical studies in target validation, assessment
of disease response, investigation of pharmacodynamic
Using the combination of an OEA GEM and GEM of OEA markers of drug action, the modeling of drug resistance and
of molecular‑imaging technologies, Wang et  al. studied the for understanding drug toxicity can each potentially improve
activation of the AKT serine/threonine kinase in response the likelihood of successful drug development. Incorporating a
to long‑term cisplatin therapy.[57] The authors showed that 6‑month transgenic mouse model into safety testing strategies
the treatment of cells in culture and tumor‑bearing animals for new drugs/chemicals makes valid scientific, ethical and
with cisplatin resulted in activation of AKT, a key mediator of sound business sense, since these assays are shorter in duration,
cell survival. On the basis of these results, they investigated use fewer animals and the cost is well below the traditional
the therapeutic use of AKT inhibition in combination with 2‑year mouse bioassay.
cisplatin, which resulted in enhanced and prolonged induction
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58. Mohammed A, Janakiram NB, Lightfoot S, Gali H, Vibhudutta A, Source of Support: Nil, Conflict of Interest: None declared.
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