Various Radioactive Isotope Research by Lathrop and
Harper |
| FISHER: |
I was still interested in just a couple of things before we move into
that.
You remember the work at Oak Ridge on gallium-67 and
gallium-72? |
| HARPER: |
Yes. They made a mistake and did a study on a patient with cancer, and
they used gallium-67 because it was carrier-free145 —and they
wanted a point with that in their curve—and [happily] it localized in the
tumor, so they were off and running [(using gallium-67)]. |
| FISHER: |
Tell us more about this. |
| HARPER: |
So everybody started using gallium for localizing tumors. |
| FISHER: |
Did you work with gallium-67? |
| HARPER: |
We made gallium-67. It was one of the first things we did when we got the
cyclotron. Apparently, we ended it [(meaning the work with gallium)]. That is,
after zinc. We were bombarding zinc, in the tank, as an internal target, and
it's supposed to be very bad for cyclotrons to have zinc bombarded in the
vacuum.
But we got away with it; the cyclotron was sufficiently
overdesigned so it didn't hurt. |
| FISHER: |
What were some of the [diagnostic or therapeutic] applications that you
tested for gallium-67? |
| HARPER: |
We didn't do anything with it [in] particular. |
| FISHER: |
You made some [(gallium-67)]. |
| HARPER: |
We made it and gave it to the clinicians to work with. |
| LATHROP: |
We didn't do any experimental work in humans [with gallium-67, but] we did
experimental animal work. |
| HARPER: |
Oh, that's right, you were working on the placenta and the placental
transfer and that sort of thing. |
| FISHER: |
The article by Gottschalk mentions use of gallium-68 EDTA.146 |
| HARPER: |
Yeah, that was off a generator. |
| FISHER: |
And that it had potential applications for brain imaging. |
| HARPER: |
Well, that's another whole business. We went to a meeting of the Society
in Montreal, [Quebec, in Canada] and Gottschalk and Anger147 —this
is when Gottschalk was working with Anger in [the University of California at]
Berkeley, and they had an exhibit on [the use of] gallium-68 localization in
brain tumors.
They pointed out that it was an extracellular fluid
labeled [with] gallium EDTA [(that they used]. So the lights came on [(we
suddenly realized how gallium could be best used) and we thought to ourselves,]
"My God, that's how pertechnetate behaves [as an extracellular] fluid
[label]!" So we came back [to our lab] and immediately started doing brain
[scans, which] worked spectacularly. |
| LATHROP: |
We had a brain scanning instrument that was made here at the Argonne Cancer
Research Hospital. |
| HARPER: |
It was designed around iodine-131 [but it worked well with 99MTc
pertechnetate]. |
| LATHROP: |
And it had just become operational. |
| HARPER: |
So we got lots and lots of brain scans. |
| FISHER: |
Did you ever work on any chromium-51 or iron-59 blood studies here at the
hospital? |
| HARPER: |
We never did. The hematologists with the whole-body counter did[,
however]. |
| FISHER: |
There was quite a bit of that kind of work that went on at Argonne Cancer
Hospital. |
| HARPER: |
Yes. We had nothing to do with it. |
| FISHER: |
Back in 19— |
| HARPER: |
You were asking about the whole-body counter at one point. The group—Leroy's
group—George Leroy148 and Carol Newton were doing— |
| LATHROP: |
—fission products. |
| HARPER: |
—fission product studies. Heating the fission products to see how
long it took them to go through [(i.e., how long they were retained in the body
prior to excretion)] at modest [activity] levels. |
| LATHROP: |
The whole-body counter—that was the original purpose of the whole-body
counter: potassium studies. And then they used it [(the counter)] for fission
product studies. And then— |
| FISHER: |
These fission product studies—what was the purpose of those studies,
to investigate the metabolism of fission products? |
| HARPER: |
Yes, how bad is it to heat fission products; how fast do you eliminate
them; that sort of thing. |
| LATHROP: |
It was not our project. |
| FISHER: |
Who were the investigators again? |
| HARPER: |
George Leroy and— |
| FISHER: |
How do you spell that? |
| HARPER: |
L-E-R-O-Y. He's dead. |
| FISHER: |
George Leroy. |
| HARPER: |
And Carol Newton. |
| FISHER: |
Newton? |
| HARPER: |
N-E-W-T-O-N. |
| LATHROP: |
She went to the west coast someplace, didn't she? |
| HARPER: |
Yes. |
| LATHROP: |
A long time ago. |
| FISHER: |
The Cancer Hospital was involved in, as early as 1953, studies with
yttrium-90 to determine whether yttrium-90 might be useful for intracavitary149
therapy. |
| HARPER: |
—in rats. You should have had a copy of a paper somewhere that showed
the irregular distribution of intraperitoneal150 colloids. We
injected yttrium chloride in saline, at body pH,151 it turns it into
hydroxide and distributed in clumps around the peritoneal cavity.
We
also looked at gold[-198] in connection with that study. That did the same
thing. |
| LATHROP: |
I don't think they have the paper, [but] I have a copy of that paper. |
| HARPER: |
Okay. Well, we have several copies. We can get it for you. Anyway, that's
what we did. It got presented at the meeting in Geneva, [Switzerland at the]
Peaceful Uses of Atomic Energy [Conference] in 1956. |
| FISHER: |
What was the extent of your human work with yttrium-90 in the peritoneum?152 |
| HARPER: |
Nothing. |
| FISHER: |
Only [work] in animals? |
| HARPER: |
Only in animals, rats. |
| FISHER: |
What was it that prevented further human application of yttrium-90
intraperitoneally? |
| HARPER: |
Lousy localization; it was very irregular. We discovered that the use of
32P in people is just as bad [and] the gold is not very good [(as it failed to
localize well in tumors)].
That's why we were led to this project
that we're involved in now, because that's the first time we found anything that
stayed fairly uniformly distributed in the intraperitoneal [cavity]. |
| FISHER: |
Did you ever do any sodium-24 studies here at the hospital? |
| HARPER: |
No. |
| FISHER: |
We came across a publication by Gould, LeRoy, and Okita, on the use of
carbon-14–labeled acetate to study cholesterol.153 |
| HARPER: |
They were looking at exhaled— |
| FISHER: |
CO [(carbon monoxide)]. |
| HARPER: |
CO. |
| FISHER: |
From cholesterol metabolism? |
| HARPER: |
Yes. |
| FISHER: |
This work with carbon-14 acetate— |
| HARPER: |
We did one study with 11C [(carbon-11)] acetate. It localizes in the heart
real nicely. It disappears. (to Lathrop) This you presented in
Copenhagen, [Denmark]. |
| LATHROP: |
Yes. |
| HARPER: |
That was the only thing we did with acetate after the dog study that I did
when I was a [medical] resident. |
| FISHER: |
Do you remember any collaborative studies? |
| HARPER: |
I remember using carbon-11. |
| FISHER: |
Using carbon-11? Do you recall any collaborative studies with the Los
Alamos people on carbon-14–labeled acetate? |
| HARPER: |
No, sir. |
| FISHER: |
Los Alamos had an interest in carbon-14 acetates injected intravenously. |
| HARPER: |
Well, that's what [Bill] Neal and I did. We thought, "We have a
world-beater here!" Acetate, you could inject, you could metabolize it into
almost anything: [it had] marvelous peripheral alimentation.154
So we tried it [(acetate)] on each other, and it causes—when you inject it
into a dog, the dog turns pink, but then he survives perfectly okay.
(laughter) |
| HARPER: |
So we tried injecting it into each other, and I was braver than Neal was
(facetiously): I injected more of it into him. It causes horrible
sensations. |
| FISHER: |
For example? |
| HARPER: |
Things turn yellow; you feel miserable. This is [with] two or three grams
[of acetate]. |
| LATHROP: |
Are these the chemical effects? |
| HARPER: |
Those are the chemical effects of acetate. |
| FISHER: |
Of acetate. |
| HARPER: |
It would not be a good thing to give for peripheral alimentation. |
| FISHER: |
No, no long-term residual effects of this? |
| HARPER: |
Oh, no, it's over in a couple of minutes. |
| FISHER: |
But it wasn't a pleasant experience? |
| HARPER: |
No, it sure wasn't. |
| FISHER: |
How did you measure the carbon-14? |
| HARPER: |
That wasn't labeled. |
| FISHER: |
It wasn't labeled? |
| HARPER: |
No, this was after our experiment with dogs, showing it was incorporated
into everything, particularly lipids. |
| FISHER: |
I see. That was just— |
| HARPER: |
So we decided to try it on each other, just as unlabeled acetate. |
| FISHER: |
Unlabeled acetate? |
| HARPER: |
Yeah. |
| FISHER: |
But it's interesting that you would mention this, because that's a good
example of a human experiment with a nonradioactive material. |
| HARPER: |
Yeah. |
| FISHER: |
Which is another thing that is difficult for young scientists to do
anymore, and that's conduct any human studies. |
| HARPER: |
There was another instance in which human studies should have been done.
You're familiar with the strontium-82/rubidium-82 [isotope] generator? The Los
Alamos people created one that worked perfectly beautifully in dogs. They would
get beautiful, gorgeous pictures of the heart [from the 82Ru images].
But what they eluted it with was strongly buffered ammonium chloride, pH 10
[alkaline]. So we got one of their generators and tried it, and it caused the
most awful pain at the site of injection and up the arm from the strongly
buffered— |
| FISHER: |
Ammonium chloride? |
| HARPER: |
Ammonium chloride. So the animal studies were meaningless; it could not be
used clinically. I could only stand it for about 30 seconds. |
| FISHER: |
Because it was so painful? |
| HARPER: |
Yes. |
| FISHER: |
Was that due to the hypertonicity155 of it? |
| HARPER: |
Yeah. Well, it was the high pH [(high alkalinity, making the solution
caustic)]. |
| FISHER: |
High pH. |
| HARPER: |
So that's another reason for doing things in people, rather than in
animals. Before you spend thousands of dollars in an animal project, you ought
to try it once on the people, on the investigator himself. |
| FISHER: |
There was interesting work on the use of labeled proteins in evaluating
multiple myeloma156 here at the Cancer Hospital. |
| HARPER: |
I have no thoughts about that. |
| FISHER: |
Using nitrogen-15–[labeled] glycine. |
| HARPER: |
Well, that's in the way of getting away from [using] radioactivity. |
| LATHROP: |
Who are the authors? |
| FISHER: |
Well, it's not easy to determine, but—Hardy and Putnam. Did you know
them? |
| HARPER: |
No. |
| FISHER: |
At the University of Chicago back in early 1950s—Putnam, Meyer, and
Miyake.157 |
| HARPER: |
No. They escaped us. |
| FISHER: |
Working with—would the cyclotron have been the source of the
nitrogen-15? |
| HARPER: |
That's inert. |
| FISHER: |
It's inert? It's a stable isotope? |
| HARPER: |
Yeah, nitrogen-13 is something else. We had a big project going on that
[subject]. |
| FISHER: |
Well, I'm glad you told me that, because I will correct that error. That's
stable nitrogen. |
| HARPER: |
Yeah. Used in the mass spectrometer.158 There's a fair amount
of work going on with carbon-13 and nitrogen-15, doing metabolic studies. |
| FISHER: |
Well, they also did work with carbon-14–labeled glycine. |
| HARPER: |
I'm sure. |
| FISHER: |
It looks like—and compared it to carbon-14, and used L-lysine. All
right. Also, here at the hospital, carbon-14–labeled digitoxin was used in
some studies [done by] Okita, Plotz, and Davis, do you remember?159 |
| HARPER: |
(to Lathrop) Do you remember back then? |
| FISHER: |
Recall any of that work? |
| HARPER: |
This is out of the Argonne Report. Jake offered to make me Director of the
Argonne Cancer Hospital at one point. |
| FISHER: |
Who did? |
| HARPER: |
Jacobsen. |
| FISHER: |
Jacobsen. What was his first name? |
| HARPER: |
Leon. |
| FISHER: |
Leon Jacobsen.160 |
| LATHROP: |
He was the one who was the first director of ACRH. |
| HARPER: |
He was the [spleen] shielding man. He was a hematologist. He was dean at
that point. I said, "I'm sorry, I wasn't interested in other people's
research." You have to be, if you're going to direct an operation like
that. |
| LATHROP: |
He was the person who actually got the Argonne Cancer Research started. |
|
Argonne Cancer Research Hospital History (Early
'70s) |
| YUFFEE: |
This might be an aside, but I was curious, in trying to get an idea of the
history of the Research Hospital. We know when it started. Then we know, in 1971
it became the Franklin McLean Institute. Is that good? |
| HARPER: |
That was when DOE [(the U.S. Department of Energy)] took—I mean,
Atomic Energy Commission turned into DOE. |
| YUFFEE: |
Okay, so around '74? |
| HARPER: |
It was around then that the mission [of ACRH] nominally changed. |
| FISHER: |
Well, it was ERDA,161 actually. |
| HARPER: |
ERDA, that's right. |
| FISHER: |
Energy Research and Development Administration decided— |
| HARPER: |
I forgot about that, yes. |
| FISHER: |
—decided not to continue directly funding human therapy at its four
hospitals. |
| HARPER: |
Right. |
| FISHER: |
One [hospital] of which was Argonne. |
| YUFFEE: |
Does the Franklin McLean [Institute] still exist under that name? |
| HARPER: |
Well, it's chiseled in granite on the front of it. |
| YUFFEE: |
And so it's still— |
| HARPER: |
It's a geographical term now. |
| YUFFEE: |
Okay, so it has been included, incorporated, into what general part of the
hospital system, now? |
| HARPER: |
Well, yes; its laboratories. |
| YUFFEE: |
Oh, I see, so it sort of doesn't exist as its own— |
| HARPER: |
—not as a hospital. Well, it's— |
| YUFFEE: |
—geographic. |
| HARPER: |
The former director thinks it does, but it really doesn't. |
| LATHROP: |
It's all part of the [University's] Department of Radiology [in the
Pritzker School of Medicine] now. |
| YUFFEE: |
Okay, so now it's included in the Department of Radiology? |
| HARPER: |
Well, that's only the third—no, Hematology is on the second floor,
and other things are on other floors. It's not all Radiology. |
| YUFFEE: |
So it just exists now, in a geographic sense, as the Franklin McLean
[Institute]. |
| HARPER: |
That's correct. |
| YUFFEE: |
Thank you. |
|
Research on Brain Tumor Imaging Agents |
| FISHER: |
Do you remember some work by Tocus, Okita, Evans, and Mullan on the use of
iodine-131–labeled fluoroxene as a brain tumor imaging agent?162 |
| HARPER: |
Only very, very vaguely. |
| FISHER: |
Did that ever pan out? |
| HARPER: |
I don't think so. |
| LATHROP: |
No, that predated the brain scanner. |
| HARPER: |
Pertechnetate wiped off most of everything in terms of brain scanning
agents. [(It was more effective than anything else under study.)] |
| FISHER: |
Did it? |
| HARPER: |
Yeah. Took a long for Monte Blau—you knew Monte Blau?163 |
| FISHER: |
I didn't know him. |
| HARPER: |
He was strongly opposed to the technetium business, because it was "unphysiological."
Katherine went and gave a long speech to them.
(laughter) |
| HARPER: |
To [our collaborators at Roswell Park Memorial Institute in] Buffalo, [New
York,] and convinced them. I presented it at the Nuclear Medicine [Association]
meeting in Florida. Monte Blau got up and said, "It's a bad agent, because
it doesn't show the tumors, it [only] shows the normal brain."
I
said, "Yes, it's a bad agent, but it's the best we've got." |
| YUFFEE: |
That's an interesting anecdote. |
|
|
|
| LATHROP: |
Monte Blau once stated that [you could image anything] with radioactive
peanut butter.
(laughter) |
| HARPER: |
No, that was the liver and kidneys you could image with radioactive peanut
butter; anything goes to the liver and anything goes to the kidneys. |
| YUFFEE: |
That's funny. |
| HARPER: |
He made that [remark] at the Pittsburgh meeting [of the Society of Nuclear
Medicine]. |
| FISHER: |
You mentioned Leif Sorensen. He did a study in 1960 here at the hospital
using strontium-85 chloride— |
| HARPER: |
No recollection. |
| FISHER: |
—administered to seven adult subjects. |
| LATHROP: |
For what purpose? |
| FISHER: |
To study the metabolism of strontium and calcium. |
| HARPER: |
Good heavens. |
| FISHER: |
[They] also did some work with calcium-47 together in that study, which
you probably weren't aware of that or familiar with. |
| LATHROP: |
Strontium is actually where I got started; back in the Manhattan [Project,
Metallurgical] Laboratory days, we were doing strontium studies in animals.
But in the course of reading through the literature, I found that there were
two people, investigators in England, who had given themselves doses of
strontium and then recovered their excreta and analyzed it. So, this is a way of
doing things without being radioactive, but it's a lot easier [to study
metabolism] if it's radioactive. |
| FISHER: |
Absolutely. |
| HARPER: |
You left out a couple of big areas [of our research]; are you still
planning to come back to them? |
| FISHER: |
I don't want to leave anything out, and I would like you to, if you can
think of something right now that we haven't discussed, go ahead and bring it
up. |
| HARPER: |
Well, [our research with] nitrogen-13. |
| YUFFEE: |
We actually did have that on the list, the last [question] on the list
here. |
| HARPER: |
Oh. I [was a] consultant to the people at Sloan Kettering,164
who have a little [research-size] cyclotron like ours. We were interested in
nitrogen-13 because we found that we could make, by bombarding methane [to
produce] rather impure ammonia, nitrogen-13 ammonia.
The people at
St. Louis had been looking at nitrogen-13 ammonia, and they found it went in the
liver and brain, but they completely missed the fact that it also goes to the
heart. So we started a series of studies of the heart, got the cardiologists
interested in this.
And then the people at Sloan Kettering discovered
that a much better way to make the nitrogen-13 ammonia was to bombard water
protons165 and get a (p, ) reaction166 on oxygen. It
made nitrate, which could then be reduced to ammonia very easily.
We
used this extensively on several hundred patients, collaborating with the
cardiologists, looking at fresh infarcts,167 old infarcts, people
with angina, unstable angina, and so forth, doing the sort of studies that one
would do with thallium, only with a ten-minute half-life.
So we would
make the stuff and run it across the hospital, image the patients; it worked
beautifully. |
| FISHER: |
By imaging the photon, the 0.511[-MeV] photons. |
| HARPER: |
Yes. In order to do this, we had to develop a special collimator168
for the camera, which we made out of tungsten. The high-energy camera resolution
is sufficiently good that it showed the individual holes in the collimator; so
we developed a collimator that was a little bit off-center and rotated [while
imaging and] that eliminated the hole pattern without hurting the image. |
| FISHER: |
Were normal subjects used for some of these nitrogen-13 studies? |
| HARPER: |
Only us. |
| FISHER: |
Only Dr. Harper and Mrs. Lathrop? |
| LATHROP: |
These were the ones we mentioned earlier, about the heart scans. |
| FISHER: |
Okay. |
| YUFFEE: |
Oh, where they found the lesion? |
| LATHROP: |
Yes. |
| HARPER: |
The people at UCLA169 really latched onto this. They've been
using it vigorously. |
| FISHER: |
For their PET170 imaging? |
| HARPER: |
Yes. |
| FISHER: |
Yes, that's true; they're some of the world leaders in this field. |
| HARPER: |
That's right. I think we started it, but they picked up on it, and they
had much better equipment for doing it. |
| FISHER: |
Well, they're taking advantage of the dual detector system [for positron
emission tomography (PET)]. |
| HARPER: |
Yeah. That's right. |
| FISHER: |
In coincidence [(simultaneous detection of both photons from a single
decay event)]? |
| HARPER: |
Correct.
|
