"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."
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