THE STIMULUS TO HYPERTROPHIC GROWTH
101
Probably the greatest obstacle to the experimental study of growth is
the lack of a sensitive method of measuring growth rate. Some early workers
determined the change in ratio between tissue weight and body weight.
This method is very insensitive to small changes in growth rate unless it
is used over long experimental intervals, and the results are made uncertain
by random individual variation in body proportions. Moreover, the weight
measured is not necessarily all protoplasm.
As we have discussed above, the rate of growth of liver and kidney is
probably only one factor influencing the mitotic rate in these tissues. After
a variety of experimental procedures Survis and Kennedy (1963) have
observed a stimulation of rat liver mitosis which was not associated with an
increase in liver mass. However, the mitotic rate has been used extensively
as a measure of growth rate. The mitotic rate is always measured indirectly.
The method which was used most frequently until recently is the determination of mitotic index, the fraction of the cells in a tissue section which
show mitotic figures. The tissues are fixed with or without the previous
injection of colchicine into the experimental animal. The use of the mitotic
index as a measure of mitotic rate depends on the assumption that the
duration of the observable phase of the mitotic cycle is constant. Any
experimental intervention which changes the duration of this phase will
change the mitotic index without necessarily changing the mitotic rate.
There is a marked circadian rhythm of mitotic activity in most tissues,
which must be carefully controlled in any comparison of mitotic indices
(Blumenfeld, 1938; JafTe, 1954).
The use of colchicine in quantitative studies of mitotic rate is very
questionable. The statement is sometimes made that colchicine in suitable
dosage arrests mitoses at metaphase by inhibiting spindle formation.
Malinsky and Lang (1951) have studied the change in observed mitotic
index in rat liver as a function of dosage of colchicine. They found no
plateau of response until lethal doses of the drug were given. This means
that any experimental intervention that alters the distribution of the
standard 1 mg/kg dose of colchicine in the body of the experimental animal
will alter the observed mitotic index without affecting the mitotic rate. In
addition, colchicine has been observed to stimulate (Teir, 1944), and in
another case to inhibit (Brues and Cohen, 1936), mitotic activity and to
mimic the action of sex hormone (Havas, 1939). Adrenaline has been
reported to counteract the action of colchicine on mitosis (Evensen, 1964).
The use of colchicine introduces so many extraneous variables into any
experimental situation that its benefits (raising the observed mitotic index
and reducing the number of cells which must be examined in order to
obtain an adequate statistical certainty) are generally overshadowed. However, after careful studies have been made of the effects of the drug, it may
well prove useful in tissues other than liver.
101
Probably the greatest obstacle to the experimental study of growth is
the lack of a sensitive method of measuring growth rate. Some early workers
determined the change in ratio between tissue weight and body weight.
This method is very insensitive to small changes in growth rate unless it
is used over long experimental intervals, and the results are made uncertain
by random individual variation in body proportions. Moreover, the weight
measured is not necessarily all protoplasm.
As we have discussed above, the rate of growth of liver and kidney is
probably only one factor influencing the mitotic rate in these tissues. After
a variety of experimental procedures Survis and Kennedy (1963) have
observed a stimulation of rat liver mitosis which was not associated with an
increase in liver mass. However, the mitotic rate has been used extensively
as a measure of growth rate. The mitotic rate is always measured indirectly.
The method which was used most frequently until recently is the determination of mitotic index, the fraction of the cells in a tissue section which
show mitotic figures. The tissues are fixed with or without the previous
injection of colchicine into the experimental animal. The use of the mitotic
index as a measure of mitotic rate depends on the assumption that the
duration of the observable phase of the mitotic cycle is constant. Any
experimental intervention which changes the duration of this phase will
change the mitotic index without necessarily changing the mitotic rate.
There is a marked circadian rhythm of mitotic activity in most tissues,
which must be carefully controlled in any comparison of mitotic indices
(Blumenfeld, 1938; JafTe, 1954).
The use of colchicine in quantitative studies of mitotic rate is very
questionable. The statement is sometimes made that colchicine in suitable
dosage arrests mitoses at metaphase by inhibiting spindle formation.
Malinsky and Lang (1951) have studied the change in observed mitotic
index in rat liver as a function of dosage of colchicine. They found no
plateau of response until lethal doses of the drug were given. This means
that any experimental intervention that alters the distribution of the
standard 1 mg/kg dose of colchicine in the body of the experimental animal
will alter the observed mitotic index without affecting the mitotic rate. In
addition, colchicine has been observed to stimulate (Teir, 1944), and in
another case to inhibit (Brues and Cohen, 1936), mitotic activity and to
mimic the action of sex hormone (Havas, 1939). Adrenaline has been
reported to counteract the action of colchicine on mitosis (Evensen, 1964).
The use of colchicine introduces so many extraneous variables into any
experimental situation that its benefits (raising the observed mitotic index
and reducing the number of cells which must be examined in order to
obtain an adequate statistical certainty) are generally overshadowed. However, after careful studies have been made of the effects of the drug, it may
well prove useful in tissues other than liver.