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CAM & Life Style > A Mouse is not a Man (or Woman)

Last update: 08/12/2015

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A Mouse is Not a Man or a Woman | Related Resources

Here are some thoughts from Bill R., an advisor to PAL, who's been testing cancer compounds in mouse models for 30+ years.

A Mouse is Not a Man or a Woman

"A mouse is not a man (or woman).  The behavior of a drug in a mouse need not be the same as in a human. Meaning, the drug may distribute differently, proportional differences per blood and organs and tumor, in mouse vs. man. Drug exposures ( the amount of drug and for how long) in different body parts , including tumor, may be quite different in mouse vs. man. 

Such differences between species can dictate the relative efficacy (activity vs. the tumor) vs. toxicity (activity against normal tissue) of a drug in those different species. Different species will not only have, potentially, different exposures associated with varied distributions, but also different metabolism pathways for the drug. 

How the drug is changed by enzymes within each species dictates how the drug is metabolized, not only how quickly but in which  directions. Some metabolites may be active, and contribute to a drug's overall activity. Some metabolites may, not usually, but sometimes, also be toxic. 

Mouse and human may show differences in how they metabolize drugs; sometimes the differences are important, sometimes not. Such differences in metabolism could also then affect the routes of excretion of a drug and its metabolites.

A human tumor growing in a mouse is an artificial system.  We know  that, but its a still a useful test system. 

The human tumor that grows in a mouse need not be an exact replicate of the tumor removed from a patient. Different tumor cells may thrive preferentially in a mouse  compared to those present originally in the patient, so that the tumor growing in a mouse may reflect only a portion of the total cellular mix contained in the original patient tumor. 

With increasing passage over time, either in a test tube or in a mouse, the tumor cells which survive the experience will be those selected to do well in whatever laboratory  environment is used for propagation. Eventually, the tumor may still  be "human", but it may not be exactly the same as when it was removed 
from the patient. 

A tumor is affected by its environment, its blood supply, the nutrients and growth factors present in its host of origin (the patient). When the environment is changed, as when a patient's  tumor is put into a laboratory mouse, the impact of that change may  affect a drug's activity. 

Tumors typically kill because they metastasize. While human tumors will grow in athymic* and other immunocompromised host mice, they do not, typically, or as aggressively,  metastasize, like they do in patients.

*A laboratory mouse lacking a thymus gland. Athymic mice have no T cells and useful in research because they do not reject tumor or other cells transplanted from mice, humans or other species.

Oral administration of a compound to a mouse, may or may not, correlate with, or predict successfully for, a similar degree of  activity and toxicity (or inactivity) in humans administered the compound orally. 

While the reasons for differential effects between species may be many, the predominant first factor to consider is the  amount of bioavailability, or absorption, of the compound that occurs in mouse and man. ...

You may feed a mouse pure diet of compound X, but if compound X isn't absorbed, it won't enter the bloodstream and be distributed throughout the body. And, if a portion of the orally consumed drug does get into the mouse, the same degree of absorption may not occur in humans." 

~ Bill Rose (advisor)

 

Related Resources

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Amer J Translational Research 2014:
Lost in translation: animal models and clinical trials in cancer treatment http://1.usa.gov/1Np5DyL

"the average rate of successful translation from animal models to clinical cancer trials is less than 8%. "

"Despite successful pre-clinical testing, 85% of early clinical trials for novel drugs fail; of those that survive through to phase III, only half become approved for clinical use [3]. The largest proportion of these failures occurs in trials for cancer drugs [4]. Furthermore, fewer than one in five cancer clinical trials find their way to the peer-reviewed literature, generally due to negative findings [5]. Although logistical and study design issues are often identified as the root cause of clinical trial failures, most futilities in fact originate from molecular mechanisms of the drug(s) tested [6]."

 
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Cancer immunotherapy: insights from transgenic animal models
 
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Maximizing mouse cancer models

"Crucial features of the tumour microenvironment that are altered or lost in xenograft tumours include nearby normal tissues, stromal cells, vasculature and lymphatic circulation, and immune cells.

"Immune system. Both the adaptive and innate immune response are crucial modulators of tumorigenesis through a complex interplay between inflammation and immunosurveillance that promote and inhibit tumour growth, respectively118, 119. These intricacies make it impossible to accurately model tumorigenesis with animal culture models in immunodeficient mice.

To date, humanizing the murine immune system has consisted of ablating the endogenous immune system followed by engraftment with human immune cells120; however, species-specific differences in both the adaptive121 and innate122, 123 immune systems can confound interpretations.

 

 

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