|
|
| FISHER: |
One of the interesting things that I came across was your use of
thallium-199 as a heart-scanning agent.
(laughter) |
| HARPER: |
That's an interesting story. |
| FISHER: |
Now, you didn't have positron124 detectors at that time, did
you? |
| HARPER: |
No. |
| FISHER: |
Thallium-201, I'm thinking of. |
| HARPER: |
Yes. The "eye people" called me up one day and said, could I make
them some radioactive potassium, because they had been reading. [The
ophthalmologists] were interested in thallium localization, because thallium
apparently localizes in pigmented tissues in the eye; it localizes differently
in the eyes of white rabbits and black rabbits.
They wanted to use
radioactive potassium, because the potassium and thallium ions behave somewhat
similarly, and they wanted to use potassium to trace thallium.
We
said, "My God, if you're going to trace thallium with potassium, you can
certainly trace potassium with thallium." So we were off and running with
thallium. We made some thallium on our little cyclotron by bombarding mercury.
It was a horrible mix, and that's where the thallium-199 came in. |
| LATHROP: |
We couldn't make the [thallium]-201 in our cyclotron. |
| HARPER: |
We didn't have a big enough cyclotron. So we went ahead and tried it
[(thallium-199)] on a couple of people. One of them was Mrs. Lathrop, and one of
them was a gentleman that had a melanoma [(skin cancer)]. We said, "Aha,
melanoma! This should tie in with the eye people, a pigmented lesion. It should
pick up the thallium." |
| FISHER: |
Thallium has a half-life of seven hours. That would seem to be quite
suitable. |
| HARPER: |
Well, it was a mixture—I mean, if you bombard mercury, you can see
what you could get. |
| FISHER: |
Sure. |
| HARPER: |
So we tried it and what did we get? A good picture of the heart. So that's
what we presented to the Society for Nuclear Medicine, [and] that stimulated the
people at Brookhaven to make thallium-201. |
| LATHROP: |
(to Harper) What we got [when you tried it on me,] was a great,
big hot [radioactive] spot. You decided that my clothes were contaminated.
Remember? |
| HARPER: |
No. |
| LATHROP: |
Well, you did.
(laughter) |
| LATHROP: |
So I had to start peeling them off [(my clothes)]. |
| FISHER: |
What activity levels were used for these initial studies with
thallium-199? For example, Katherine, you say you were a subject of one of these
early experiments. How much [radio]activity would you permit going into your
blood veins for this early study? |
| HARPER: |
A [few] millicuries. |
| LATHROP: |
Well, you know, it's not a matter, exactly, of how much activity. It also
is what the quality125 of the activity is, average— |
| HARPER: |
How much do you need? |
| LATHROP: |
Yeah, that's right, too. |
| FISHER: |
Thallium-199 has several higher-energy photons. |
| LATHROP: |
But we had already—we must have done some animal experiments. |
| HARPER: |
I don't remember what we did. |
| FISHER: |
It sounds like you were the subject of an experiment on several occasions.
|
| LATHROP: |
Yes. |
| HARPER: |
We both were. |
| FISHER: |
Was this accepted practice, still, in that particular era? |
| HARPER: |
Still is. |
| FISHER: |
Still is? |
| HARPER: |
You don't give anything to a patient that you haven't tried on yourself,
[that] sort of idea. |
| LATHROP: |
That's right. I would tell the people that I had asked to volunteer that I
wouldn't ask them to do anything I wouldn't do to myself. And one day, one of
the people I was working with said he really appreciated that. That was the
reason that he decided that he would volunteer for the studies that we were
doing. |
| FISHER: |
Incidentally, this was really quite recently, in 1970, when you worked on
thallium-199. I say "recently," because this is not too far back in my
own memory. |
| HARPER: |
That's right. Well, we didn't advocate thallium-199 as an [imaging] agent.
It was a study showing that thallium did localize in the heart as we thought it
was going to. I mean, the agents that were used before were cesium and rubidium
and potassium, and the thallium fit in there [(that category)] because it
behaved in a somewhat similar manner metabolically. |
| FISHER: |
Of course, now, thallium-201 is a widely used cardiac imaging agent. |
| HARPER: |
Of course. We're still doing dosimetry126 on it. |
| LATHROP: |
We discovered [something] with the thallium. I was a subject and Paul was a
subject, and my scan had a lesion, and his didn't. That puzzled him for a while,
until we found out that I actually did have a lesion, which had subsequently
gone away. |
| FISHER: |
When you make thallium in the cyclotron, you make a mixture of thallium
isotopes? [Did] you get thallium-201 or thallium-202? |
| HARPER: |
We did a thallium-202 study. We bombarded mercury and let the short-lived
thing [nuclides] decay out until there was only the thallium-202 left, and then
we were able to do a long-term biodistribution study using whole-body imaging
system, and that's on its way to the MIRD Committee127 at the
moment, I think[, but] that was some years ago. |
| FISHER: |
About what year was the thallium-202 study? |
| LATHROP: |
Well, that was after it had become used widely in clinical practice. |
| FISHER: |
Thallium-202 is a positron emitter with some photons— |
| HARPER: |
[No, it decays by electron capture as listed in Lederer.] We were looking
at photons. |
| LATHROP: |
We wanted to be able to follow the thallium for a long period of time.
|
| HARPER: |
We did it in a whole-body counter128 that was [modified] to
image [high-energy photons]. |
| FISHER: |
Who were the subjects of this study? |
| HARPER: |
One subject. |
| FISHER: |
Dr. Harper? |
| LATHROP: |
No. |
| HARPER: |
No, this was one of our technologists; he was captive personnel. He knew
what was going on. His family [complained] when he kept his excreta in the
icebox [(refrigerator)] at home.
(laughter) |
| LATHROP: |
Because we had followed him for six or eight weeks. |
| YUFFEE: |
That's fair [to complain under those circumstances]. |
| HARPER: |
Well, this is just to check on the whole-body counter, because we didn't
really trust that. So we collected excreta and added them up to look at the
disappearance [of radioactivity]. |
| FISHER: |
We see in the published literature many references to the whole-body
counter. |
| HARPER: |
Yes. |
| FISHER: |
Sometimes it's not clear where the whole-body counter is. Is this Argonne?
|
| HARPER: |
It's the one here. |
| FISHER: |
It's the one here at the hospital? |
| HARPER: |
Yes. |
| FISHER: |
You have your own [counter] here in the Argonne Cancer Hospital? |
| LATHROP: |
We did. |
| HARPER: |
We did. It broke and it has been [dismantled]. Its use has been
discontinued. |
| FISHER: |
But the hospital had its own whole-body counter for many years. |
| HARPER: |
Yes. |
| FISHER: |
Do you remember how long that operated? |
| HARPER: |
Maybe 20 years. |
| LATHROP: |
It died when we were doing the OIH129 study. The first study we
did with it, was [with selenomethionine.] |
| HARPER: |
Yeah. Mrs. Lathrop followed a [patient] for three years who had an ordinary
diagnostic dose of selenomethionine. That's the number-one MIRD dose estimate.
|
| LATHROP: |
There's the selenomethionine dose estimate report I think that I put into
that packet. |
| FISHER: |
Yes. |
| LATHROP: |
Well, that was our first study, but the reason the whole-body counter was
constructed was to do potassium studies. |
| HARPER: |
Most of our progress was made back before the regulators [(institutional
review boards, or IRBs)]130 got into the act. |
| FISHER: |
You know, I'm envious because— |
| HARPER: |
You should be. |
| FISHER: |
—in today's science, it's not only difficult to discover things
because you've made so many fantastic discoveries already, but it's also hard—
|
| HARPER: |
Well, it was an open [research] field. Nobody had done the legwork. We
lucked out. |
| FISHER: |
It's hard to get [research] funding, and I think you and many others who
did the work during this particular era, 1940 through 1980, were able to
discover so many new and exciting things.
When you make thallium by
cyclotron, do you also end up with some long-lived thallium-204 contaminant?
|
| HARPER: |
[In the present commercial system, thallium-203 is bombarded with
high-energy protons, producing a (p-3n) reaction,131 giving
lead-201. Contaminating lead-202 decays rapidly to thallium-202, which is
removed on a column. The longer-lived lead-201, then decays to thallium-201 and
is removed from the column, leaving the contaminating lead-203.] |
| FISHER: |
You worked originally with mercury as a source for thallium, didn't you?
|
| HARPER: |
Yes, we did. That's because—that was the only way we could do it.
|
| FISHER: |
Okay. But now, is it made— |
| HARPER: |
Yeah. You bombard the thallium-203, and it makes lead-203, lead-202, [and]
lead-201. Now, what do you do? This is short-lived [(half-life: 8.4 hours)].
Okay. So you let these decay out and it leaves you with lead-201, and then you
milk it off the thallium-201. |
| FISHER: |
I see. That's interesting. So you have a tradeoff between yield and
purity. |
| HARPER: |
Sure. |
| FISHER: |
Have you been able to register any patents? |
| HARPER: |
We haven't attempted to. |
| FISHER: |
Haven't attempted? |
| HARPER: |
It's just too much hassle. |
| LATHROP: |
The University [of Chicago] was not really receptive to it until just
recently. Now, they are urging people to [file invention reports]. |
| HARPER: |
Somebody patented the technetium process, the methyl-ethyl-ketone
extraction. |
| LATHROP: |
That was [the chemical firm] Union Carbide [Corporation]. |
| HARPER: |
Union Carbide did. And we were advised that it was just a patent to
discourage other people; it wasn't a real patent, [but] a ghost patent of some
sort. |
|
|
|
| FISHER: |
I'm interested in work you did in 1966, or maybe a little earlier than
that. |
| HARPER: |
I know what that was. |
| FISHER: |
On the use of antifibrinogen132— |
| HARPER: |
Oh, that. |
| FISHER: |
—labeled with iodine-131 for cancer therapy. |
| HARPER: |
That's—you're familiar with the [William F.] Bale133 and
[Irving] Spar134 operation? |
| FISHER: |
Bale was at Rochester.135 |
| HARPER: |
Yeah, the whole operation is there. And so was Spar. He ended up as Dean
[of Graduate Studies and Financial Aid]. |
| FISHER: |
Can you tell us more about this history? |
| HARPER: |
The idea was that when clots formed, the fibrinogen was carried down [as
fibrin. Labeled antifibrinogen would then be carried down to the fibrin of the
clot.]
Then, if you discourage fibrinolysis136 by giving
[amino caproic acid]— the localization shows up better. [Bale and Spar]
even thought that it might be possible to get up to therapeutic levels.
They had to have special 131I made at Oak Ridge, because there are some inert
iodines made by the usual reaction that reduces the specific activity.137
I don't remember exactly how they did it, but they got the special run of
high-specific-activity 131I.
They labeled the antifibrinogen, and
then [to purify it,] they absorbed this out onto a fibrin column, and then
eluted138 it. They had a [stricter] IRB in Rochester, so they
couldn't [carry out patient] studies, and we could.
So that's how the
collaboration developed. We did a number of studies. We even did a therapeutic
one. |
| FISHER: |
Can you describe the subjects of these studies? |
| HARPER: |
We were trying to look at localization in people with advanced malignancy.
|
| FISHER: |
Okay. So your subjects were cancer patients? |
| HARPER: |
Yes. They were not treatable otherwise; and there was a possibility
of treating them.
We did one experiment in a lady that had advanced
ovarian carcinoma. We gave [her] antifibrinogen, and then, after it had
localized, we wiped out the [remaining] circulating antifibrinogen by giving
[anti-rabbit goat] gamma globulin.139 There was no problem.
It gave us [improved image] quality because it wiped out the circulating
activity, which all went into the liver and metabolized and the iodine was
excreted. |
| FISHER: |
What were some of the cancer types that this [therapy] was conceived for?
|
| HARPER: |
Anything. Anything that's outgrowing its blood supply and producing
incipient140 necrosis, [and then] laying down the fibrin. |
| FISHER: |
What would be some good examples of that? |
| HARPER: |
Any tumor. |
| FISHER: |
Any solid tumor. |
| HARPER: |
Yes. We presented this at a meeting in Germany, and the Germans leaped onto
it; somebody in Berlin, in East Germany, did 50, 60 patients. It [(the therapy)]
seems to work best in sarcomas.141 |
| FISHER: |
Was this work discontinued after some time, for any reason? |
| HARPER: |
Well, we got tired of it. [We] got interested in other things. |
| LATHROP: |
Well, didn't it [(the fibrinogen therapy)] work sometimes better than it
did other times? |
| HARPER: |
Yeah. It wasn't 100 percent. |
| FISHER: |
Were you able to achieve high enough amounts—administered amounts for
therapeutic efficacy—or were you limited in some way? |
| HARPER: |
Well, we thought—no, we weren't limited in any way, it was just a
matter of how much activity— |
| FISHER: |
—you could get? |
| HARPER: |
Yes. The people at Rochester made the material and shipped it to us in dry
ice [(frozen carbon dioxide)], so it's really an offshoot of their study. |
| FISHER: |
So you were only limited by the amount of labeled antifibrinogen that you
could obtain. |
| HARPER: |
That's right. I mean, you can give hundreds of millicuries of 131I without
it doing any very serious damage if you don't worry about regulations. |
| FISHER: |
Katherine, were you involved in the dosimetry of any of those patients?
|
| LATHROP: |
Of the antifibrinogen patients? |
| FISHER: |
Yes. |
| LATHROP: |
No. |
| HARPER: |
We weren't particularly worrying about dosimetry. We were just looking at
what actually [happened]. |
| FISHER: |
Localization and— |
| LATHROP: |
Now, whether—what was his name—Spar? |
| HARPER: |
Who—Irv Spar? |
| LATHROP: |
Irv Spar, yes. He may have done something on that. I don't know. Do you?
|
| HARPER: |
I don't remember. |
| FISHER: |
This is interesting because, you know, now, with the advent of— |
| HARPER: |
Yes. Well, I think this is the first [clinical monoclonal antibody142
studies] that I'm aware of. |
| FISHER: |
Now, with the advent of highly specialized [antibodies]— |
| HARPER: |
No, the pathologists, [at our institution], were doing things with
antibodies in rats, curing tumors in rats, but I don't think they ever got to
the point of using it clinically. |
| FISHER: |
Clinically. With highly specific monoclonal antibodies, iodine-131,
high-dose iodine-131 therapy is becoming more and more successful. |
| HARPER: |
People are getting more and more enthusiastic about it, but that doesn't
always follow. |
| FISHER: |
The physicians are really doing quite well, now, with high-dose iodine-131
antibodies in conjunction with bone-marrow transplantation and— |
| HARPER: |
Oh, I see. |
| FISHER: |
. . . [and with] chemotherapeutic143 agents, all in
combination to form a very potent attack [on malignancy]. |
| HARPER: |
Sounds like it's almost worse than the disease. |
| FISHER: |
It's a heavy dose for a disease that won't be [effectively] treated any
other way, I guess. |
| HARPER: |
Right. |
| FISHER: |
But the pioneering efforts here, I'm sure, were very, very important in—
|
| HARPER: |
Have you ever seen them referenced? I have them. |
| FISHER: |
Yes. |
| HARPER: |
Okay. |
| FISHER: |
I have that in this package. |
| HARPER: |
Good. |
| FISHER: |
Which was really, [it] really caught my attention. |
| HARPER: |
Okay. Well, that's your special interest, [or] one of your special
interests. |
| FISHER: |
And so I was interested in asking about any follow-up [therapy]. |
| YUFFEE: |
It's on that [subject that] I did have one quick question. You mentioned
that part of the origination of your collaboration at Rochester was that you
didn't have a strict IRB and they did [have a strict IRB]. |
| HARPER: |
Yes. |
| YUFFEE: |
Was that the basis of other collaborations? |
| HARPER: |
No. |
| YUFFEE: |
Just in that one instance? |
| HARPER: |
Just that one instance; it must have originated in a conversation at a
meeting. |
| YUFFEE: |
And that sort of goes to the heart of what you were saying [about] the
advent of more and more regulation getting in the way [of research]. |
| HARPER: |
More and more regulations makes it tougher and tougher [to get work done].
|
| FISHER: |
During this period, Dr. Harper, did you continue to practice surgery?
|
| HARPER: |
Oh, yes. I ran a service, you know, from the "reactor to the grave."144
(laughter) |
| FISHER: |
That's a quotation that could live on. What were your main interests?
|
| HARPER: |
General surgery. |
| FISHER: |
General surgery? Do you still do that, or are you retired? |
| HARPER: |
No, no. I haven't done it [(surgery)] for 10 or 15 years. |
| YUFFEE: |
This might be a good time, Darrell, to go through some of the [other]
experiments we [need to discuss]. |
