Selenium Tumor-Imaging Studies (Early '70s) |
| YUFFEE: |
I don't think we've talked about metabolism studies with the selenium.
|
| HARPER: |
Selenium? |
| FISHER: |
We will come to selenium. |
| HARPER: |
Okay.
I don't think we told the anecdote about how we failed
to do the brain scans. This is back in the days when pertechnetate was the new
wonderful thyroid imaging agent, and we were working on that. We had a patient
who was supposed to have a carcinoma of the thyroid with a brain metastases.
|
| FISHER: |
What year would this have been about? Do you remember? |
| HARPER: |
Well, before we did any brain scanning. |
| LATHROP: |
It would have been— |
| HARPER: |
It was before the Montreal meeting of the Society [of Nuclear Medicine].
|
| FISHER: |
Okay. |
| HARPER: |
So we did a brain scan on him to see if we could see this carcinoma of the
thyroid, [but] no sign of the carcinoma of the thyroid, just what you would
expect to see in a normal brain scan. We looked at the brain scan and said, "This
doesn't look like a brain scan," and abandoned the whole idea of brain
scanning.
(laughter) |
| LATHROP: |
Until you looked at— |
| HARPER: |
—until we ran across Gottschalk's study with gallium-68 at Montreal.
|
| LATHROP: |
And then you went back and got out the scan. |
| HARPER: |
Yeah, I know, [and] we've been showing it ever since; that was a couple of
years there.171 |
| FISHER: |
Was this ever written up? |
| LATHROP: |
No. It just never— |
| HARPER: |
No, [but] it has been presented on occasion. [On a trip to Rome, Italy, I
sat next to Jim Richards,] and I didn't hear him talking about technetium. [At
the time, I was pursuing 125I.] |
| FISHER: |
Some of the best ideas, Paul, are those that we learn from others and then
apply ourselves in some other way. |
| HARPER: |
Yeah, it needs to be triggered properly. We decided that the UCLA people
had grabbed that and leaped on with it. |
| YUFFEE: |
I don't think we finished [talking] about selenium. |
| FISHER: |
We're going to go on to selenium-75. |
| HARPER: |
(to Lathrop) Okay, selenium, that's your department, Katherine.
|
| LATHROP: |
What do you want to know about selenium? |
| FISHER: | Well, first of all, what were the events— |
| HARPER: |
Mrs. Lathrop spent some years in the Poisonous Plant Laboratory172
at Laramie, [Wyoming] and that's where the selenium story started. |
| FISHER: |
Okay, that's where we should begin, then.
(laughter) |
| LATHROP: |
Well, I'm not really sure about that. You want to know how selenium got
started; is that it? |
| FISHER: |
Yes, tell us the selenium story.173 |
| LATHROP: |
All right. From my viewpoint, as far as nuclear medicine is concerned, it
got started with Monte Blau. |
| FISHER: |
B-L-A-U? |
| HARPER: |
Right. |
| LATHROP: |
That's right. |
| HARPER: |
He's one of the people you should be interviewing. |
| LATHROP: |
Yes. |
| HARPER: |
He's a pioneer. |
| LATHROP: |
Because he was looking for something that would localize in the pancreas,
and the amino acids174 have a way of doing this, and he [also]
wanted something radioactive. Sulfur does not have a radioactive isotope that
was suitable, so he happened onto selenium-75; it worked reasonably well for
those times. |
| HARPER: |
Well, it [(the form)] was as selenomethionine. |
| LATHROP: |
—yeah, as selenomethionine. He labeled the methionine with selenium
in place of the sulfur. |
| HARPER: |
With the help of yeast. |
| LATHROP: |
Yes. |
| HARPER: |
It was a biological labeling[, a natural labeling process rather than one
devised by man]. |
| LATHROP: |
Now, I guess this was about the time that the [MIRD] committee was working
up to doing dose estimate reports, because, as you know, all the early
publications were absorbed fractions of this, that, and the other thing that
actually went into— |
| HARPER: |
Yeah. The selenium, of course, has a 50-day half-life—or it's a
120-day half-life [(biological half-time for excretion)]. |
| FISHER: |
About 120 [days]. |
| HARPER: |
One hundred and twenty. And in the study where you use selenium, you look
at it 45 minutes after injection. So this is a little disproportionate [compared
to the time selenium takes to clear the body]. |
| LATHROP: |
We had access to the whole-body counter that we talked about this morning,
so we decided that we would try to do a study. We did some animal studies and we
decided that we would try to do a study [on] Mr. Fields. [That was your patient,
wasn't it?] |
| HARPER: |
No, I don't know whose patient he was, but he ended up being yours.
(laughter) |
| LATHROP: |
No, not really, only [for] the study. He was a very, very nice, dignified
black man, and we talked to him about what we were doing and the reason we were
doing it [(to understand its metabolism rate {retention, distribution,
clearance, etc.})]. |
| HARPER: |
Well, he had the selenium scan [as a routine clinical study]. |
| LATHROP: |
Yes. |
| HARPER: |
[We administered] 200 microcuries of selenomethionine [(75Se) to him].
|
| LATHROP: |
And it [(the selenium scan)] was just a matter of our making use of the
selenium that he had; we didn't give it to him just for our purposes. As Paul
said, it was for clinical use.
But he came back. First it was day
after day, I guess, and then it got to be intervals of weeks, and, finally, a
month or so apart. And this went on for almost three years and we were still
able to get valid [radioactivity] counts.
We had some problems when
we started out [with this research], because of the [low count rate] recovery
[of selenium] that we were getting. We found that this was due to the placement
of the detectors; that was useful, we [then] wanted to design a better-type
instrument.
Paul said something about the Poisonous Plant
Laboratory. When I was living in Wyoming, I worked for the Poisonous Plant
Laboratory.
In the West, selenium was a big problem, because a herd
of cattle would go through a pasture, and maybe half of them would die before
they got to the other side of it because of the selenium[, natural in the soil,]
that was concentrated in the plants that the animals ate. So I had that interest
in selenium too, which made it more interesting to me to do this study on a
human. And that is the data, part of which made up the dose estimate report for
selenomethionine [(data from the patient study mentioned above)].175
The other was short-term data that we fed the information that I got from the
other contributors to the data.176 |
| FISHER: |
How is it [(selenium)] evaluated in humans? |
| HARPER: |
Imaging. |
| LATHROP: |
Well, no. I think he means if we did—were images made and looked at,
or what kind of data of that sort? |
| HARPER: |
The only [numerical] data we got out of it was the whole-body count. |
| LATHROP: |
That's all we got out, but what about the people that were doing it
clinically? |
| HARPER: |
Oh, they just looked at pictures. |
| FISHER: |
So the pictures weren't really used for— |
| HARPER: |
Quantitation.177 |
| FISHER: |
Quantitation and liver uptake. |
| HARPER: |
No. |
| FISHER: |
Fractional retention, retention half-times? |
| HARPER: |
No. |
| LATHROP: |
No, in those days, people were so happy to get an image; that was really
all they cared about. |
| HARPER: |
Now, it's pretty close to the same today.
(laughter) |
| LATHROP: |
Well, okay, yes, to some extent, because there are an awful lot of things
that could be done with nuclear medicine besides making images, [namely studying
the biokinetics, pharmaco-dynamics, metabolism, etc., and natural physiological
processes in the body. And] they are not being done. |
| FISHER: |
Did the long half-life of selenium-75 [(127 days)] preclude its use for
most studies? |
| LATHROP: |
No. |
| HARPER: |
No, the dosimetry [(dose to the patient)] is the limiting factor, and that
was okay. |
| FISHER: |
Is it? |
| HARPER: |
It doesn't have any primary particle radiation, which helps. |
| FISHER: |
That's interesting, but it does persist in the human for a long time.
|
| HARPER: |
Oh, yes, it's an essential metabolite; cattle get white muscle disease if
they don't have selenium. |
| LATHROP: |
There's a disease called kwashiorkor; it's a disease where children become
very, very thin, and [can] die [from selenium deficiency]. |
| FISHER: |
(leafing through background materials he had brought to the interview)
I was going to see if I could find that—here it is: the selenium dose
report. |
| HARPER: |
Yeah, you can see the disappearance curve [(the curve plotting selenium
retention over time)] published in there somewhere. |
| FISHER: |
[Determined by] whole-body counting. |
| HARPER: |
Yes. |
| FISHER: |
That's interesting. |
| LATHROP: |
We also did excreta collections on that one [(selenium-75)] too, in the
early part of the [study]. |
| FISHER: |
Is this a compound that's used very much anymore? |
| LATHROP: |
No, not for some years. |
| HARPER: |
Oh, no, it has been abandoned long ago. This brings us to a whole new
question about, how do you deal with the pancreas? |
| FISHER: |
Yes. |
| HARPER: |
Because of this interest in the pancreas, we had a major interest in
looking at possible agents.
As Mrs. Lathrop mentioned, the amino
acids go to the pancreas. We worked up a number of amino acids with carbon-11
and put them in mice, [and] every single amino acid we made went to the pancreas
in the mouse.
Then we formed a [collaboration] with one of our
surgeons here who was enthusiastic [and] was willing to tackle carcinoma of the
pancreas by excision [(surgical removal by cutting out)], which is something
that has been pretty-well abandoned, [yet] he was still enthusiastic about it.
So, in the course of this, we collected maybe 100 patients that he
allowed us to image, and we used various different amino acids we [had]
synthesized with carbon-11 in the carboxyl position. The one that worked best we
[studied] in one patient. We went through the business of separating out the
optical isomers using a column [(to use a pure preparation of the designed amino
acid)]. |
| FISHER: |
(smiling) The one patient being Katherine Lathrop. |
| HARPER: |
(smiling) Yes. |
| FISHER: |
Why was she different than the others? |
| HARPER: |
(smiling) She was available. So we [used] D-tryptophan,
L-tryptophan, and D-L-tryptophan [(various amino acids)]. |
| LATHROP: |
There was something that I particularly wanted to do— |
| HARPER: |
And the localization with D and L is markedly different. [D-form] goes a
lot to the liver, a lot to the kidneys; the L-form goes to the pancreas and not
to the kidneys and not to the liver. And so, this turned out to be the ideal
imaging agent.
Well, it turned out that pancreas imaging had moved
ahead so that CT [(computerized tomography)]178 studies and MRI179
studies and ultrasound180studies [had replaced] nuclear studies.
|
| LATHROP: |
If you're looking for a mass— |
| FISHER: |
—in the pancreas. |
| LATHROP: |
Yes. But if you're looking for physiologic function, nobody is interested.
|
| HARPER: |
Nobody was interested in looking at physiologic function in the pancreas
so that [research] died; but it was interesting. |
| LATHROP: |
But it's still out there. Maybe some day, somebody will [continue the
research]. |
| FISHER: |
You know, but this whole story of investigating selenium,
selenomethionine, is very interesting.
(reading from a reference book) I see how we spell kwashiorkor:
K-W-A-S-H-I-O-R-K-O-R, "a protein malnutrition disease of animals."
|
| LATHROP: |
—and people. |
| FISHER: |
Oh, I'm sorry—"and children." All right. |
| HARPER: |
Okay. |
|
Other Isotope Research |
| FISHER: |
What are some of the other interesting isotopes that you've worked on that
you haven't mentioned? |
| HARPER: |
Indium. |
| FISHER: |
Indium-111? |
| HARPER: |
No, indium-113m. |
| FISHER: |
-113m? |
| HARPER: |
It's short-lived—[(It has a short half-life.)] |
| LATHROP: |
Shall we tell him the story about that? |
| HARPER: |
We're about to. |
| LATHROP: |
Okay, well, go ahead. |
| HARPER: |
Indium-113m, this was Henry Wagner's favorite isotope; it's the daughter
of a tin [isotope]. |
| LATHROP: |
Tell them how he started using it. |
| HARPER: |
I don't know how he started using it. |
| LATHROP: |
Well, Dr. Harper mentioned [the surgical resident] George Andros earlier,
who worked with us on technetium. George's wife was an artist, [and] George was
sort of impressed by all these radionuclides that we would have, so his wife
made up a poster that said, "Isotope of the Week," and she would have
[on] it whatever [isotope] we happened to be working [with]. [So], she made up a
poster that indium was the isotope of the week. Henry Wagner's chemist came by
for a visit, I forget his name right now, and he saw this [poster] on the wall,
but he didn't say very much about it. But it wasn't too long until Henry Wagner
was working on indium [and] he was making quite a big thing of it; it was going
pretty well.
(to Harper) Now, do you want to tell him the part about the
comparison paper? |
| HARPER: |
Yes. |
| LATHROP: |
Okay. |
| HARPER: |
Well, there were three short-lived isotopes with long-lived parents that
were possible to make into generators [for] general use; indium-113m was one of
them. Somebody finally figured out how to put it on a [chemical-separation]
column so that the tin stayed and the indium came through.
Gallium-68
was another one, with germanium as the parent; then there was technetium[, but]
there was some question which would be the best one to use, other things being
equal.
So we made up a bunch of phantoms,181 imaged them
with these different isotopes using [the] appropriate methods. [Then, we]
calculated the radiation dose and the figure of merit being the statistical
probability of detecting the material in a lesion like this and a background
like this.
The figure of merit, divided by the dose, gave you a
figure for comparing the various agents; indium didn't do very well, and Henry
Wagner never forgave us [for letting our poster lead him to think indium-113m
help special promise].
(laughter) |
| FISHER: |
I was wondering what the attraction was with indium-113m. |
| HARPER: |
It's a short-lived isotope. |
| FISHER: |
It has a 97-minute half-life. |
| HARPER: |
Yeah, well, that's okay. It also has a huge amount of conversion
electrons. |
| FISHER: |
Right. |
| HARPER: |
But it [(indium-113m)] was used very widely: commercial generators were
peddled, and it had a long half-life parent, so it could be used for a long
time. |
| FISHER: |
That's right. |
| HARPER: |
So it was a useful agent, but the [photon] energy was pretty high, so it
was hard to image well. |
| FISHER: |
About 392 keV [thousand electron-volts]? |
| HARPER: |
That's right, and it's difficult to image anything that way [with]
commercially available collimators. |
| FISHER: |
Did you do work with [the] indium-111 I mentioned that just a little bit
earlier? |
| LATHROP: |
We did some work with indium-111, some placental studies with it. |
| HARPER: |
Yeah, Mrs. Lathrop was unable to sell the hard-nosed gynecologists on the
specific localization in the placenta of indium. |
| LATHROP: |
Early on in the use of indium, somebody said that it was just blood pools
that they were seeing [in radiological images] when indium was in the placenta,
but it really isn't: it actually localizes there. |
| FISHER: |
In embryonic tissues? |
| HARPER: |
In the placenta. |
| LATHROP: |
In the placenta itself. |
| FISHER: |
In the placenta itself? |
| LATHROP: |
Yes. |
| FISHER: |
Why is that? I don't know the mechanism for that. |
| LATHROP: |
I don't know why. |
| HARPER: |
It was an observation. |
| FISHER: |
But it's clearly the placenta? |
| HARPER: |
Yes. |
| LATHROP: |
Oh, yeah, we did lots of animal studies [that involved] taking out the
placenta. |
| HARPER: |
[In] guinea pigs, you could see half a dozen little placentas in the
pregnant [animal]. |
| LATHROP: |
I have a nice slide of that someplace. |
| HARPER: |
But the gynecologists never bought it—they started using ultrasound
instead. |
| LATHROP: |
In a way, it's too bad, because there again, it shows the physiology that
the [ultrasound] images won't show. |
| HARPER: |
Yes, we had this monkey with a sick placenta [on which] we demonstrated
[the problem] before we took it out. |
| FISHER: |
Now that's interesting. |
| HARPER: |
I don't know if we worked with anything else diagnostically. |
| FISHER: |
Well, I'm going over—you've worked with so many different isotopes.
|
| HARPER: |
Which ones have we dropped through the cracks? |
| FISHER: |
It's hard to know which ones we haven't really covered. I would like to
just ask another question about cesium-131— |
| HARPER: |
Oh, yes. |
| FISHER: |
—and wonder if you could say a few more [words] about that. |
| HARPER: |
Oh, cesium-131, that dates back to when we were redoing implants,182
and it was a nice agent to fit into an implant, because it has low-energy
emissions—pure electron catheter. |
| FISHER: |
I read the paper on that. |
| HARPER: |
We also had a go at cesium-130 [when] we were trying to look at the heart.
Cesium localization in the heart is slow, [because] it's not first-pass
localization, the way many of the agents are. [It localizes in the heart muscle,
which is viable.] |
| FISHER: |
What was the chemical form of the cesium? |
| HARPER: |
Ionic; it's a potassium analog. [It behaves in the same way as potassium.]
|
| FISHER: |
I was wondering if you didn't have a lot of background [mass to serve as
contrast] from normal muscle. |
| HARPER: |
There isn't much normal muscle in the chest wall. |
| LATHROP: |
There was an interesting story about the cesium, no fall in the production
of it. (to Harper) You remember the discrepancy on the isotope tables?
(Harper chuckles.) |
| FISHER: |
(to Harper) That brings a chuckle from you. |
| HARPER: |
Yeah, [because] the Segrè183 chart had a cross-section
value for cesium and—for barium-131, but the [precursor]—the thermal
neutron capture cross-section was such and such, and it turned out it [(the
chart's prediction)] was quite wrong, and we were able to demonstrate it. |
| LATHROP: |
He started working on it, and then he decided he would go out to ANL and
talk to the people out there. |
| HARPER: |
Yeah, they looked at the Segrè chart and looked at me pityingly and
said, "You don't really want to do this, do you?" But the Oak Ridge
isotope catalog had the correct cross-section. |
| FISHER: |
You know, I don't think this interview would be complete unless we
discussed alpha emitters and your interest in alpha emitters as a therapeutic—
|
| HARPER: |
Well, these are the last couple of months [that we have been doing that
research]. |
| FISHER: |
Well, what is your age? |
| HARPER: |
How old am I? Close to 80. |
| FISHER: |
Close to 80 and still branching into new research. I think that's
remarkable.
Alpha emitters are particularly effective in cell
killing, so they offer something that beta emitters don't. |
| HARPER: |
Right, well, we talked a little bit about auger emitters; I got into those
first. |
| FISHER: |
But not so much on this order, this was during our lunch. |
| HARPER: |
Okay, it's not on the auger emitters? |
| LATHROP: |
The alpha emitters, that's where you're interested in, isn't it? |
| FISHER: |
Well, we're interested in both. |
| HARPER: |
Okay. |
| FISHER: |
Let's start with auger emitters, then. What auger emitters have you worked
with, other than iodine-125? |
| HARPER: |
123. |
| FISHER: |
Iodine-123? |
| HARPER: |
That's because it's available, and you can use it, although it's pretty
expensive. We've [also] been trying to make bromine-80m. Arnie Friedman thought
[this] up. Arnie was not as fussy about [the hazards of] his isotopes as we
were; he didn't object to the fact that the 4-hour bromine-80m had a 17-minute
daughter, bromine-80, which had strong beta and gamma emissions.
So
we decided to go ahead with that and ignore the daughter. We thought possibly,
that if the bromine-80m were attached to an estrogen and got into a cell,
disintegrated, that probably the excitation would [have] an effect sort of like
the [Szilard–Chalmers] reaction:184 It would release the
daughter bromine so it would go out and circulate around the body, and be vastly
diluted, and probably wouldn't cause too much trouble.
Dr. DeSombre
in the Ben-May Laboratory has been pursuing this to some extent, along with Jeff
Schwartz. They've been able to demonstrate clearly that bromine-80m, when it's
incorporated into the DNA185 molecule as BUdR186 is vastly
destructive to the [DNA and] produces lots of chromosome breaks. |
| FISHER: |
It has a high LET?187 |
| HARPER: |
Of course. |
| FISHER: |
At the short-range? |
| HARPER: |
That's right, it's similar to the heavy-charge particle with just a very
short range. DeSombre has also shown—I think he used 123I for this, or the
estrogen 125I—when it's localized in the estrogen receptor, which is in the
cell adjacent to the DNA, [it] will also cause significant cell killing. |
| FISHER: |
Now, the obvious applications for this would be— |
| HARPER: |
—well, tumors that carry estrogen receptors. |
| FISHER: |
Ovarian? |
| HARPER: |
—ovarian, breast. |
| FISHER: |
Cervical? |
| HARPER: |
Not cervical, [but] endometrial188 [tumors are another
application]. |
| FISHER: |
I see, endometrial. |
| HARPER: |
And I think, vaginal, [but] I'm not sure about that. And then there are,
of course, prostate [tumors, whose treatment] might work with androgen. These
are things that are being thought about. |
| FISHER: |
Have any of these studies advanced to the clinical stage? |
| HARPER: |
No, no, this is still all at mouse and cell level. |
| FISHER: |
But it sounds very productive for the future. |
