ISOTOPES IN MEDICINE*
GRACE MEDES, P H . D .
From The Lankenau Hospital Research Institute and The Institute for Cancer Research,
Philadelphia, Pennsylvania
It has been suggested that the greatest benefit to the human race to be derived
from the application of nuclear energy may well prove to be the use of isotopes
in medicine and in the solution of biochemical problems upon which the science
of medicine is based.
More than fifty years have elapsed since the discovery of radioactivity. Its
powerful physiologic effects were almost immediately revealed through injury
to some of the earliest investigators. The application of this knowledge to the
treatment of cancer soon followed, even before physicists had begun to comprehend the nature of the radiations emitted.
Today our knowledge of the structure of atoms and of the forces involved in
their transformations is still meager.
We know that an atom consists of a positively charged nucleus surrounded
by whirling, negative bodies called electrons. The nucleus is composed of
neutrons and protons, the former being electrically neutral while each proton
bears a positive charge of one unit, which exactly neutralizes the negative charge
on one of the orbital electrons.
The nucleus occupies only about a thousandth of the space of the atom but
contains nearly all of the mass, since the weight of each proton and each neutron
is approximately 1840 times that of one electron. As atoms are electrically
neutral, it follows that there must always be present equal numbers of protons
and electrons. Each element has its own characteristic number of these, ranging
from one of each in hydrogen, the lightest known element, to uranium, the
heaviest known naturally occurring element, with 92 protons and electrons.
Hydrogen contains no neutrons, while uranium contains 146, which with its
92 protons, give it a weight of 238.
The number of positive charges on the nucleus, or the number of protons, is known as the atomic number. Hydrogen is designated as l l i 1 , the
subscript on the left referring to the atomic number and the superscript on the
right representing the atomic weight. Uranium is written, 92U238, i.e.,
92 protons U 9 2 P r o t o n s + 1 4 6 neutrons Obviously, the difference between the
atomic weight and the atomic number is equal to the number of neutrons.
Each of the elements lying between hydrogen and uranium in the atomic
table possesses its own characteristic number of protons and electrons and
therefore has its own specific chemical properties. Addition of a proton to the
nucleus, and necessarily also an electron to its orbits, steps the element up one
place in the atomic table, while loss of one reduces it to a position next below.
This process is known as transmutation, since a different element is formed.
* Received for publication, November 24,1947.
354
1S0T0PJSS IN MEDICINE
355
Alteration in the number of neutrons does not affect the number of electrons,
wherefore the chemical properties are unchanged, only the weight is affected.
Atoms with identical chemical properties and different atomic weights are called
isotopes.
Isotopes are produced by bombarding atoms with various particles derived
from other atoms, neutrons, protons, or loose combinations of them, such as
alpha particles, which consist of two neutrons and two protons, and hence have
a positive charge of two. Deuterons, consisting of one neutron and one proton,
and therefore bearing a positive charge of one, also are employed frequently.
The colliding particle may remain in the nucleus of the element bombarded or
it may pass through with, or without, knocking out some portion of the nucleus.
The newly formed atom may be stable or it may be so unstable as to break down
immediately. In still other cases disintegration may occur over a measurable
period of time, ranging from less than a minute to billions of years. For each
element and set of conditions a characteristic change occurs. Disintegration
takes the form of ejection of some definite nuclear constituent, an alpha particle,
a beta particle (an electron from a neutron) or a gamma ray, emitted when
internal rearrangements take place. This disintegration represents the change
by which an unstable atom goes over to a stable form. These disintegrating
elements are termed radioactive elements.
Bombardment, by which these isotopes are produced, occurs spontaneously
in nature from the action of radioactive elements in ores or may be accomplished
in the laboratory by essentially the same process in cyclotrons. Today isotopes
are being prepared in chain-reacting uranium piles by neutron bombardment
and may be acquired in quantities a thousand to a million times as great as can
be procured in a cyclotron. Unstable, or radioactive isotopes of relatively short
life, must be produced artificially in these ways but stable isotopes, formed also
in nature, slowly accumulate and need only be separated from their more common
isotopes.
Methods of separation are based upon the only property in which they differ,
weight. A variety of technics are in use, depending mostly upon differential
rates of diffusion under set conditions; but, since differences in weight are slight
(e.g., methane, C 12 H4, has a molecular weight of 16 while methane, C 13 H4, has
a molecular weight of 17), separation is slow and in actual practice involves many
repetitions of the same process.
''
Methods of quantitative determination of the isotopes vary according to
whether or not they are radioactive. In case they are radioactive, they are
measured with a Geiger-Muller counter which registers the number of explosions
per second, some instruments even flashing a light and ringing a bell at each
count. Stable isotopes are determined for the most part in a mass spectrograph. Here again relative weights (mass) is the critical property.
The accompanying table lists the isotopes which have been most commonly
used in biologic work. In the several columns are given the mass (atomic
weights), the relative abundance in nature of the stable isotopes and the halflife of the unstable ones. It may be seen that in general, addition of one or two
356
MEDES
neutrons to the nucleus permits stability of the isotope, whereas further addition
means instability (radioactivity). Loss of one neutron nearly always gives rise
to an isotope of high instability, and hence of very short life.
TABLE 1
S O M E N A T U R A L AND R A D I O A C T I V E
ELEMENT
MASS
RELATIVE
AI1UNDANCE
ATOM
El.U.F-Ul'l'.
K L1C Ml-: N T
MASS
Per cent
11
C
N
99.99
0.01
—
30 yr.
10
11
12
13
14
—
8.8 sec.
21 min.
15
16
17
18
19
0
Na
P
21
22
23
24
29
30
31
32
98.9
1.1
—
—
lO'-lO 5 yr.
—
9.9 min.
99.63
0.37
—
—
—
—
99.76
0.04
0.20
—
—
—
—
23 sec.
3yr.
—
—
100
Ca
126 sec.
31 sec.
—
s
8 sec.
—
100
RELATIVE
ABUNDANCK
ATOM
HALF-UFK
per cent
—
'—
1
2
3
13
14
15
16
ISOTOPES*
Fc
—
14.8 hr.
4.6 sec.
2.6 min.
I
—
14.3 days
* D a t a from R. D . E v a n s in Medical Physics.
31
32
33
34
35
36
39
40
41
42
43
44
45
46
48
49
53
54
55
56
57
58
59
124
126
127
128
130
131
>131
—
3.2 sec.
95.1
0.7
4.2
—
—
—
0.02
—
SS days
—
4.5 min.
96.97
S.5 days
0.64
0.15
2.06
—
—
—
ISO days
0.003
0.19
—
—
2.5 hr.
—
8.9 min.
6.04
4 yr.
91.54
2.11
• 0.28
—
'—
—
—
47 days
—
—
4 days
13 days
100
—
—
25 min.
12.6 hr.
8 days
2.4 hr.
Chicago: Year Book Publishers, 1944.
Two general types of investigations with isotopes in physiology and medicine
are now being pursued. The first is their employment to supplement or supplant x-rays for bombarding tissues. A vast field of research is just being
opened up, as it is not as yet certain whether the effects produced by irradiation
differ fundamentally according to the type of particle emitted. The effects
ISOTOPES IN MEDICINE
357
vary with the rate of disintegration and the penetrating power of the ejected
particles, factors which are characteristic of each element. The amount of
the isotope which finds its way to the tissue selected for irradiation varies with
the specific element and the compound into which it has been introduced.
Thus, it is apparent that to investigate many combinations of these factors
adequately, considerable work must be done. But, if the array of possibilities
seems bewildering, it must be remembered that the very multiplicity of combinations of these factors opens up just that much more hope for the
beneficial application of isotope radiation to therapy.
Phosphorus (P 32 ) has been used most extensively in investigations of cancer
treatment. Its half-life, 14.2 days, which means that in 14.2 days one-half
of it will have decomposed and in several months all excess radioactivity will
have disappeared from the body, is especially suitable. The hardness of its
rays is such that it has sufficient penetrating power, about 0.7 cm. of tissue,
for it to be useful. Since phosphorus accumulates in rapidly growing tissues
and in the bones, where the concentration of phosphorus in exchangeable form
is high, it was hoped this radioactive isotope might prove beneficial in the treatment of leukemias in general. In a recent critical survey of the status of P 3 2
therapy, Reinhard and co-workers31 conclude that "radioactive phosphorus is
probably the best therapeutic agent available at the present time for polycythemia vera. Complete hematologic and almost complete symptomatic remissions can be produced with P 3 2 in the vast majority of patients, and remission
from a single course of treatment may last for from six months to a year or
longer."
These authors further conclude that the effect of P 3 2 on the clinical course of
patients with acute or subacute myelogenous leukemia and those with chronic
lymphatic leukemia is about the same as with x-radiation. Acute lymphatic
leukemia and monocytic leukemia are not favorably influenced by P 3 2 therapy.
Further, they conclude that Hodgkin's disease, lymphosarcoma, reticulum
cell sarcoma and multiple myeloma respond less favorably to P 3 2 than to xradiation.
The advantages of radiophosphorus administration over roentgen radiation as
summarized by Hall and Watkins17 are: (a) relative ease of administration,
(b) absence of radiation sickness and symptoms of toxicity, and (c) simplicity
with which the dose can be controlled. The disadvantages are: (a) high cost
of radioactive material, (b) bone-marrow injury in case of overdosage, and (c)
the possibility of producing a terminal, acute leukemia.
Radiosodium (Na 24 ) has been employed in the treatment of leukemia. Because of the type of its transmissions (0 particles and y rays) and of the generalized distribution it assumes throughout the extracellular and intracellular fluid,
its effects resemble those of spray roentgen therapy.
Radioactive strontium (SrS9) has been used to irradiate osteogenic sarcoma
and bone metastases from carcinoma of the prostate. Pecher26 employed as
high as 10 microcuries, and found no toxic effect and no histologic modification
of bone six months after irradiation. The radiation was most concentrated
358
MEDES
where the osteoblastic process existed. He concluded26 that on account of the
fairly good yield of radioactive strontium that can be produced in the cyclotron,
the suitable energy of its rays, and its convenient half-life, it has provided a
specific method for irradiation of the skeleton. Treadwell and co-workers,43
on the basis of similar studies, concluded also that the results seemed to justify
the therapeutic use of radiostrontium in certain bone tumors.
The employment of isotopes as biologic tracers is the second field of investigation now receiving wide attention. Here again two types of problem may be
distinguished. In the first of these, the distribution of the isotope in the body
and the rate of its deposition in tissues are used in studies of normal and pathologic growth. Those elements that show predilections for specific tissues are
proving especially valuable. For instance, iodine moves rapidly to thyroid
tissue, and the rate of its deposition may be followed simply by holding a GeigerMuller counter near the body. Perlman and his group27 •28 found that within
two hours from 11 to 17 per cent of labeled iodine fed to rats in tracer doses
appeared in the thyroid gland. Analysis showed that from 1.5 to 3 per cent
was contained in the thyroxin and as high as 16 per cent was deposited as thyroxin
in forty-eight hours.
A further refinement of this method is its extension to the radio-autograph
technic, 3 ' 18 where sections, obtained at biopsy or after sacrifice of the experimental animal following ingestion of the isotope, are compared microscopically
with photographic films against which the section has been held. In this way
the position of the isotope within tissues may be observed.
Radioiodine (I 1 3 1 and I 1 3 2 , or a mixture of both) has made possible extensive
investigations of the thyroid. It has been found that the rate of deposition is
increased in hyper- and decreased in hypo-thyroidism ;9 but, some cases of elevated and depressed metabolic rates do not show alteration in the rate of iodine
deposition and therefore cannot be ascribed to thyroid disturbance. Hence,
this test is assuming important diagnostic value.
Two radioisotopes of iron (Fe 59 and Fe 55 ) have been employed for studying the
life history and fate of the red blood cell under normal conditions 6,12,14 ~ 16 and
in various types of anemias, especially that due to blood loss.13 Radioiron was
used by Chapin and Ross4 to determine the true red cell volume of the blood.
They found it to be 8.5 per cent lower than indicated by the centrifuge hematocrit
method.
, Radioactive sodium (Na 24 ) has been used effectively in studies of mineral
metabolism in normal individuals,10 including fetal-maternal exchange8, 29 and
in many pathologic states. 38 Together with potassium (K 42 ) it has contributed
to our knowledge of water balance and ionic exchange, especially exchange
through various membrane barriers. 7, 9' u - 1 9 , 2 2 , 2 3 , 4 6
Since the distribution of strontium in bone follows closely that of calcium,26
this radioelement has been used to study the process of healing after fractures25
and after administration of parathyroid extract44 and of pituitary growth
hormone.21
The second type of tracer study is the employment of isotopes to follow the
o
ISOTOPES IN MEDICINE
359
metabolic changes of normal body constituents. Throughout the entire history
of physiologic research is scattered a series of attempts to find suitable markers
by which ingested compounds or fragments derived from them could be identified after passage through the body. Isotopes are the perfect markers. Being
chemically indistinguishable from their more common isotopic sisters, they are
utilized by cells in the relative concentration in which they and the commonly
occurring form are supplied.
Radioactive and stable isotopes are both suitable, and the choice depends
upon their relative availabilities and the conditions of the particular experiment
to be performed. The high sensitivity of the Geiger-Muller counter, as compared with that of the mass-spectrograph, permits analysis of fractions of a
microgram of radioactive compounds as against several milligrams of stable ones v
Length of life of unstable isotopes must be taken into consideration, as a half-life
of at least several hours is needed for most experiments and frequently a much
longer time is required. Hardness or softness of the rays emitted are also an
important factor, as it is by these rays that they are determined in the GeigerMiiller counter. C 14 , Ca 45 and H 3 are examples of isotopes with radiations so
soft that special technics must be employed for their quantitative determination.
When a radioactive isotope has been used, the experiment must be completed
within about ten times the half-life of the element, varying with the degree of
hardness of the rayj.
Returning to our table, let us review briefly the uses to which some of the
isotopes available for experiments of this type have been put.
Most of the pioneer work of Schoenheimer36 was carried out with H 2 , deuterium. This isotope is relatively easy to get and to measure. At first it was
used largely as a marker for the carbon atom to which it was attached. Its
usefulness here was limited since hydrogen in carboxyl, amino and other polarized
groups or adjacent to a carbonyl group, exchanges rapidly with the hydrogen
of the water. Hydrogen attached to a carbon adjacent to a keto-group reacts
slowly because of enolization and is said to be semi-labile. Today we no longer
need hydrogen for this purpose, since isotopes of carbon are available.
Isotopic hydrogen is still valuable, however, for instance, in studies of hydrogenation and also, since water enters as a component of so many chemical
reactions, heavy water is particularly useful in studying rates of synthesis and
hydrolysis.
H 3 , tritium, has not yet been widely used, possibly because it has not been
readily available. Its radiation is so soft that there is encountered some difficulty in its determination. Since the relative weights of protium, H 1 , to deuterium, H 2 , to tritium, H 3 , are as 1:2:3, the stability of the C—H 1 , C—H 2 and
C—H 3 bonds vary appreciably. In some cases, rates of reaction are so much
slower with tritium, that wide differences in the quantitative ratios of endproducts result. Hence, considerable •preliminary work must be done before
too rigid interpretations of data obtained by the use of tritium can be accepted.
C 1 1 is limited in usefulness for metabolic experiments by its short half-life,
20.35 minutes. Its short half-life is compensated for, to some extent, by the
360
MEDES
hardness of the radiations it emits. The high specific activity in which it can
be obtained, that is, the high ratio of radioactive atoms to the total number of
isotope atoms, also tends to compensate, and with careful correction for rate of
decay, C 1 1 has been a valuable tool for short-term experiments, such as those on
photosynthesis. Vennesland and co-workers45 used it to determine whether
carbon dioxide is utilized by animal tissue (rat's liver) in carbohydrate synthesis.
In this experiment, after several practice runs, sodium bicarbonate containing
C 11 was injected into a rat's peritoneal cavity, and after an interval of two and
one-half hours, the glycogen was isolated, purified, hydrolyzed, the osazone
prepared from the hydrolyzed glycogen and the C 1 1 determined all within the
five-hour deadline during which the C 1 1 retained sufficient activity for determination.
C 1 4 has largely replaced C 1 1 and is widely used. The long half-life of C 1 4 ,
estimated at approximately 5000 years,24 •30 renders it inappropriate for internal
administration to human subjects until more precise knowledge has been acquired as to the effects within the organism of long continued bombardment
with doses in tracer levels.
O 1 8 has been little used, largely because of the difficulty in obtaining it. Although this element in carboxyl, carbonyl and hydroxyl groups exchanges with
that in water, the rate is sufficiently slow so that with suitable correction, O 18
can be used to determine the mechanism of oxidation reactions. Ruben,36 for
instance, demonstrated that the oxygen expired by plants during photosynthesis
is derived from the water of the medium rather than from the C0 2 , the carbon
of which is utilized for carbohydrate synthesis.
Nitrogen has only one available isotope, a stable one, N 1 5 . With its use,
Schoenheimer36 demonstrated the lability of amino groups, even within the
protein molecule, there being a continuous exchange between amino groups of
all amino acids excepting lysine, which was not involved in this nitrogen shift.
With some amino acids the exchange took place with great rapidity, with others
it occurred more slowly. Differences in the rate of amino-group exchanges were
also found in different organs, so that degrees of reactivity of organs could be
distinguished.
Since phosphorus is a constituent of many essential cell components including
phosphoproteins, phospholipids and the various phosphorylating agents associated
with the transfer of energy, P 3 2 has become one of our most useful isotopes in
metabolic tracer work as well as in therapeutics, as mentioned above.
Two isotopes of sulfur, S 34 , stable, and S 35 , radioactive, are available for
tracer work. Since sulfur is a constituent of all protein, labeled sulfur in addition
to labeled carbon may be used as a tracer in studies of protein metabolism.42 The
relationship of the sulfur-containing amino acids, methionine and cystine, has
been partially elucidated in the demonstration that the sulfur of methionine
may be converted to cystine sulfur41 and to taurine sulfur42 in the rat. The
conversion of methionine sulfur to cystine sulfur has been confirmed6 by the use
of the stable isotope, S 34 . The more recent demonstration of sulfur in the
vitamins, biotin and thiamin, and in some of the important antibiotics such as
ISOTOPES IN MEDICINE
361
penicillin, together with suggestions that it plays a role in the activity of some of
the hormones and of many of the enzyme systems, opens up a field of special
interest for the use of the radioisotope. The turnover of thiamin and the fate of
its sulfur in a human subject has already been studied2 by injecting thiamin synthesized with radioactive sulfur.
The researches of Schoenheimer carried out largely with deuterium and N 1 5 ,
immediately initiated a new era in our concept of metabolic processes by demonstrating that organs and tissues cannot be looked upon as static structural units,
but merely parts of one grand chemical system in which distinctions cannot be
drawn between structural and metabolic components. He used the term "dynamic equilibrium" to express the idea that both synthetic and degradative
reactions were occurring simultaneously with intermediary metabolic fragments
forming a so-called "metabolic pool" from which reactions could proceed in many
different directions. A demonstration of such a series of phenomena could not
have been made without the use of markers like isotopes.
The present-day extension of Schoenheimer's work emphasizes this basic conception. One of the fields that has been intensively investigated with the aid of
isotopes is the metabolism of fatty acids. Previously, it could not be demonstrated whether this group of substances was available for reactions in the body
other than degradative and oxidative, leading to the release of energy for work.
With labeled carbon, largely C 13 , it has been demonstrated that 2-carbon fragments, derived from the fatty acid molecule, may take part in many diversified
processes such as the synthesis of cholesterol,1 fatty acids,32 succinic acid,37 citric
acid,39 glutamic and aspartic acids,33 glycogen20 and uric acid.40
In addition, a new conception of the metabolic relationship of carbohydrate
and fat has evolved from the demonstration that in the final steps of oxidation,
the carbohydrate fragment acts as a catalyst in the complete oxidation of the
2-carbon residue. Since derivatives of amino acids also enter as components of
this catalytic system, we see a tying together of the metabolism of these three
great classes of food-stuffs, carbohydrate, protein and fat, a relationship that has
been a field of speculation since the earliest metabolic studies in man and in the
experimental animal.
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