Chapter: 03 New Research in the Department of Developmental Therapeutics
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Dr. Bodey begins this segment by recalling that Developmental Therapeutics was a unique place devoted to research on the diagnosis and treatment of leukemia patients. He comments on the role of pharmaceutical companies such as the Beecham Group and Pfizer in providing institutions with antibiotics for testing. He studied the effect of carbenicillin on pseudomonas (a gram-negative bacteria) resulting in a drop in mortality from seventy or eighty percent to twenty percent. He notes other research project, his interest in chemotherapy, and the role of the NCI in supporting work on antibiotics.
Dr. Bodey then explains that he had very good relationships with the drug companies. Only on rare occasions did he have to refuse a drug company’s request to do or say something because it seemed unethical. He speculates on why the situation has changed since the sixties.
Dr. Bodey then quickly sketches his work on antibiotic combinations, explaining why pairing drugs can work. He covers the problem of resistance and how drug resistances can be specific to an institution. Dr. Bodey next notes a big problem for leukemia patients: they will start out with bacterial infections and then get fungal infections, with candida representing the biggest problem. He explains hepatosplenic candidiasis.
Dr. Bodey tells an anecdote from his residency in Seattle that shows his gift for treating infections. He was on rounds and “somehow was attuned to the fact” that a patient had candida in the liver and spleen. Dr. Bodey gave the patient an antifungal drug leading to recovery.
Dr. Bodey notes that he may have investigated the first pairing of two beta-lactam drugs, cefoperazone plus aztreonam. He notes that he studied the prophylactic use of drugs, explaining that patient at risk would often die of infection before receiving their full course of treatment for leukemia.
Identifier
BodeyGP_01_20130619_C03
Publication Date
6-19-2013
City
Houston, Texas
Interview Session
Gerald P. Bodey Sr., MD, Oral History Interview, June 19, 2013
Topics Covered
The Interview Subject's Story - The ResearcherMD Anderson Snapshot MD Anderson History The Researcher The Clinician Overview Definitions, Explanations, Translations Discovery and Success Professional Practice The Professional at Work Ethics On Pharmaceutical Companies and Industry Industry Partnerships Discovery, Creativity, and Innovation Patients Patients, Treatment, Survivors Research, Care, and Education Character, Values, Beliefs
Transcript
Tacey Ann Rosolowski, PhD:
Well, tell me about your impressions of Developmental Therapeutics when you arrived. What was the environment like for work, for research?
Gerald P. Bodey Sr., MD:
Well, it was a unique—it wasn’t really unique in the sense that I’d had the same experience when I was at the National Cancer Institute. But it was unique in the sense that in my other areas, where I took care of patients—we took care of patients; we didn’t do some research at the same time. But they had research projects on leukemic agents and so on. Having worked on infectious complications when I was at the Cancer Institute, I of course was interested in doing that here, and Dr. Freireich was also interested in having me do that. So my research was related to diagnosing and treating infections primarily in leukemia patients. The solid tumor patients didn’t get the real low blood counts and all, so we had some work. Around that time, the pharmaceutical industry began to be producing some new antibiotics, and we were able to get them. I think carbenicillin was the first antibiotic that I worked with experimentally, and that was provided by Beecham Laboratories in England. I don’t know how I managed to convince them to make the drug available to me, but I was successful, and they used to ship all the drugs from England. It was not being made here. I would get these big drums, about that high—
Tacey Ann Rosolowski, PhD:
Wow, so like three feet high.
Gerald P. Bodey Sr., MD:
And they were shipped in one gram vials of carbenicillin. Now, the dose was five grams every four hours—thirty grams a day. So that’s thirty of these little vials for one patient per day. We got to the point that we were using so much of it that we had a nurse on one of the wards spending almost the entire day just mixing up the carbenicillin.
Tacey Ann Rosolowski, PhD:
Now, how many patients did you have on one of your trials that required—? You must have required an awful lot of drugs.
Gerald P. Bodey Sr., MD:
Well, we had—I would have to look up a paper to tell you how many, but it was a substantial number. Because at the time that I started, the antibiotics that were available were either not very effective in patients who didn’t have any neutrophils or they had a limited spectrum. Pseudomonas was one of the most important infections that we were dealing with, and it was almost uniformly fatal.
Tacey Ann Rosolowski, PhD:
Now, what exactly is Pseudomonas?
Gerald P. Bodey Sr., MD:
It’s a gram-negative bacteria and very aggressive. The mortality rate at that time must have been around 70% or 80%, and it fell to about 20% to 25% with carbenicillin. I don’t know if you have my paper on carbenicillin, but—it should be in the archives over there, or I can get it. I think I may have a copy of it. I have my whole bibliography over there. I did keep a copy of a couple of papers. I think that was probably one of them, because that was one of my first major—well, it was the first major paper written on an investigational antibiotic. It had a dramatic impact. I mean, the mortality rates went from about 80% to 20%, something like that. It was really very dramatic.
Tacey Ann Rosolowski, PhD:
So that automatically became integrated into care for these patients?
Gerald P. Bodey Sr., MD:
Yes.
Tacey Ann Rosolowski, PhD:
So that was work that you did in those first years in Developmental Therapeutics. Now, what other kinds of research projects were you working on?
Gerald P. Bodey Sr., MD:
I did do—I took care of patients. I don’t know how many months of the year I was a physician in the ward, but it was a fairly substantial number.
Tacey Ann Rosolowski, PhD:
Did you find that you were seeing a much broader variety of patients?
Gerald P. Bodey Sr., MD:
When I started out, it was just patients with acute leukemia. Later on I got involved in experimental chemotherapy. I then got involved in the care of patients with other kinds of malignancies as well. Throughout my career, my major area of interest in cancer chemotherapy was in acute leukemia. I worked very closely with Dr. Freireich. He deserves the credit for all the discoveries, but I did a lot of the work with him over the years.
Tacey Ann Rosolowski, PhD:
I was curious, because you mentioned you worked on chemotherapy, what’s the relationship between the work you did on infectious diseases and the work you did on chemotherapy?
Gerald P. Bodey Sr., MD:
There wasn’t any real relationship between them, other than that the patients were getting both things. But as time went on, I got more and more involved in the cancer chemotherapy. As a matter of fact, I had to get involved right from the beginning, the first time I started taking care of patients on the ward. I mean, they were getting—
Tacey Ann Rosolowski, PhD:
Because they were getting both the chemo and they had to be treated for infectious diseases?
Gerald P. Bodey Sr., MD:
Yes. So I got interested in that. Then as time went on, that became as much of an interest to me as infectious complications. And I did a lot of—I worked with Dr. Freireich on a lot of things. Then actually, at one point in time, I was the head of the Investigational Chemotherapy Program for a while, and that involved all—whatever drugs we had. And we were heavily involved with the National Cancer Institute and their investigational drug program. That’s where we got many of our new anti-tumor agents, although some of them we got directly from the pharmaceutical industry. The antibiotics—they all came from the pharmaceutical industry. I was involved in a variety of drugs. At the time I first started out, Beecham Laboratories in England was very heavily involved with the development of new penicillin derivatives, like carbenicillin, and then there were a bunch of others. Pfizer Laboratories became heavily involved, and I had close working relationships with both of those companies, then Schoenig and a few others as well. Nowadays you’re sort of a criminal if you work with drug companies. In those days, we had a very good relationship. Nobody ever tried to get me to cheat on anything or do anything inappropriate. They were helpful in supplying the drugs and that sort of thing. I mean, I like to think of myself as being a moral person, so I would not have been involved—matter of fact, there were a couple of occasions where I wouldn’t have anything to do with something because I thought it wasn’t right or not moral.
Tacey Ann Rosolowski, PhD:
Can you tell me in a kind of sketch—? Gerald P. Bodey, Sr., MD Nothing specifically, I don’t have a very good memory of it all. I do remember that there were very few instances where I did not get involved. Occasionally there would be a drug that I would give talks—that’s also considered taboo today. But I gave a talk, not on an antibiotic; I gave a talk on infections in cancer patients. And then of course, I would discuss any new antibiotics and our experience with them. But I never felt—well, in all the years that I was involved with the drug companies, there were only maybe two or three occasions where some rep tried to get me to say something that I considered inappropriate and I wouldn’t do it. But by and large, I felt that the relationships that I had with the pharmaceutical industry were totally ethical. If they have a new drug, they’ve got to have some patients to study with it or where is it going to go? So I must have studied—I don’t know—fifteen or more new agents over the years.
Tacey Ann Rosolowski, PhD:
Why do you think the situation has changed now and the relationship with drug companies is so ethically charged?
Gerald P. Bodey Sr., MD:
Because there were some people who took advantage of things, both from the standpoint of the pharmaceutical company and from some of the doctors. They got a nice pile of money, and some of them were not totally ethical. Among the managing people in the pharmaceutical industry, I’ve never had anybody who tried to get me to do something that was unethical. I got paid for giving a talk. It wasn’t anything as high as what they’re getting nowadays. But that didn’t influence me. Certainly there was one factor, and that is that it was only the companies that had new drugs that were going to have me give a talk. I didn’t think that was something unethical. I was telling the truth. And the whole climate at that time is not what it is today, in terms of these issues.
Tacey Ann Rosolowski, PhD:
Well, it’s staggering too, the amount of money to be made nowadays with these drugs. It’s a whole other world.
Gerald P. Bodey Sr., MD:
Yeah, I got paid adequately. It was not anything like they’re paying people now. I found out that there were some people who were getting about five times as much as I was, but that didn’t bother me. I was satisfied with what I was provided.
Tacey Ann Rosolowski, PhD:
Could you tell me a little more about the different—the most important of the research projects that you worked on when you were in Developmental Therapeutics, on the antibiotics?
Gerald P. Bodey Sr., MD:
The antibiotics—oh boy, I’ll have to think a little bit.
Tacey Ann Rosolowski, PhD:
Well I could—
Gerald P. Bodey Sr., MD:
I don’t have—
Tacey Ann Rosolowski, PhD:
Let’s see. I know you did some work—I have a list of certain things. There’s one—you were saying that you did some comparative studies and then studying antibiotic combinations. What were the antibiotic combinations about? Why did you want to move to those?
Gerald P. Bodey Sr., MD:
Because the studies could extend the spectrum of activity, and in some instances the drugs interacted so that you got more of an effect than you would with either one of them alone. That was a major factor, too. It was both the spectrum of activity and the increased activity of the combination other than singularly. Then there was another factor, too, and that is if you used only one antibiotic, it was possible for the organism to develop resistance to that antibiotic, whereas if you had two, that became very, very unlikely.
Tacey Ann Rosolowski, PhD:
I was actually—I shouldn’t have been surprised, given all the advice nowadays for people to avoid taking antibiotics that are unnecessary, because of the problem of creating resistance. But I was surprised to read about the importance of resistance, and also that the resistance could be specific to an institution, which I thought was quite fascinating. Could you talk a little bit about that?
Gerald P. Bodey Sr., MD:
If it was at an institution, it is more than likely that they were using certain drugs routinely and basically all the time. In that kind of a setting, then there is potential for organisms either to develop resistance or organisms that were inherently resistant to spread. That’s one of the things that we have to be concerned about. When I started out, that wasn’t as big a problem as it became over time, because exposure to antibiotics—exposure to an organism by antibiotics that the organism was resistant to would only modestly act as susceptible for encouraging the establishment of resistant organisms in the patient. Then that patient could then be spreading it to other people.
Tacey Ann Rosolowski, PhD:
Now, how did you respond at a clinical level to that information? Did you set up a system where MD Anderson would routinely test to see if the organisms were resistant? How did that work so you understood what was going on in the institution?
Gerald P. Bodey Sr., MD:
If a patient developed fever, the first thing we did was collect specimens and see what was growing in them. Then, of course, if something grew, we would be testing, also, its antibiotic susceptibility pattern. That’s how you would get your information. Then, of course, if the patient was doing well and then all of a sudden started to have a fever again, well, then we’d be collecting specimens and looking for some other organism. One of the problems that we had to deal with was that we would start out with a patient who had a bacterial infection, and then they would get a fungal infection as a superinfection because the antibiotics didn’t have any effect on fungi. And candidiasis was the biggest culprit. I guess it still is. I wrote a couple of papers on candidiasis over the years.
Tacey Ann Rosolowski, PhD:
And I was reading hepatosplenic candidiasis—?
Gerald P. Bodey Sr., MD:
Hepatosplenic candidiasis—that was one of the first papers I wrote on fungal infections and one of the first—if my memory serves me correctly—one of the first papers I wrote when I came here.
Tacey Ann Rosolowski, PhD:
What exactly is it?
Gerald P. Bodey Sr., MD:
Candida is a fungus. Normal people get skin infections and all that. In these people without white cells and all, the organism becomes invasive and causes pneumonia, meningitis, and all sorts of things. If my memory serves me correctly, and I think it does, when I first arrived here from Seattle, they took me on rounds with the Leukemia Service. They had this patient who was running fevers, and he was obviously sick. I think he had a pretty good white count, but he just wasn’t doing well, and they didn’t know what was going on with him. I don’t know—I read the paper again recently—and I don’t know how it was that I was attuned to this, but I said, “Well, I think this man has Candida, probably in his liver and his spleen.” And that’s what it turned out to be. He ended up being treated successfully
Tacey Ann Rosolowski, PhD:
What do you treat it with?
Gerald P. Bodey Sr., MD:
I think he had actually gone into remission of his leukemia, and he just was still running this fever. So we gave him amphotericin, which was an antifungal drug. He recovered and lived for quite a while after that. I’m not sure that I have a copy, but it’s in the archives over there.
Tacey Ann Rosolowski, PhD:
I also read that you were involved with creating an animal model for Candida, that there wasn’t one before.
Gerald P. Bodey Sr., MD:
I think we’re going to have to skip over that. I don’t remember, and I don’t know that we were successful.
Tacey Ann Rosolowski, PhD:
Okay. We were talking briefly about the antibiotic combinations, and I had two. I’m not sure I’ll be able to pronounce it right, so you can correct me—cefoperazone, aztreonam.
Gerald P. Bodey Sr., MD:
Aztreonam—I don’t know if there was anything particularly magical about that. It just happened that when a new drug becomes available you want to study it. Aztreonam is a penicillin derivative. Cefoperazone is a cephalosporin. Cephalosporines and penicillins have a lot in common in terms of their activity and susceptibility and their lack of significant serious toxicities. They’re called beta-lactam antibiotics because of their basic structures and beta-lactam chemical structures. I think that was probably one of the first, if not the first, study looking at two beta-lactams in combination.
Tacey Ann Rosolowski, PhD:
What was significant about that?
Gerald P. Bodey Sr., MD:
Because usually you used some other chemical structure in your second antibiotic. You would use a beta-lactam and maybe an aminoglycoside, which was a totally different chemical structure. But to use two beta-lactams together was a bit unusual. Tacey Ann Rosolowski Why did you choose to pair them?
Gerald P. Bodey Sr., MD:
Because it was available. Cefoperazone was a broad-spectrum cephalosporin, and we’d had good results with it. How I decided to come up with cefoperazone plus aztreonam, I’m not quite sure anymore, other than it being a rather unique combination at that time to use those two beta-lactams in combination.
Tacey Ann Rosolowski, PhD:
Do you recall what the results were?
Gerald P. Bodey Sr., MD:
I’d have to look it up in my bibliography. I think it turned out quite well, but that’s a long time ago. Nobody’s using that anymore.
Tacey Ann Rosolowski, PhD:
I bet. Also, I have down fluconazole versus a placebo.
Gerald P. Bodey Sr., MD:
Fluconazole versus a placebo.
Tacey Ann Rosolowski, PhD:
How does your memory serve? It’s probably much more accurate.
Gerald P. Bodey Sr., MD:
Well, no, it may well be that it was a prophylactic study rather than a therapeutic study. Fluconazole was an oral or intravenous antifungal preparation against Candida, not so much some of the other fungi like Aspergillus, but against Candida. The nice thing about it was that it had very little toxicity, whereas drugs like amphotericin and the other antifungal drugs were all fairly toxic drugs.
Tacey Ann Rosolowski, PhD:
I guess that leads to another issue, which were the studies of therapeutic drugs for once the patient had these infections versus the prophylactic use of them. And what did you find? How did you approach studying how prophylactic drugs should be administered? What were some of the criteria?
Gerald P. Bodey Sr., MD:
We certainly wouldn’t be going around to the average cancer patient. We would use the patients who were at high risk of developing infection when they were undergoing their treatment. Of course, one of the problems that we face with diseases like acute leukemia and the patients that didn’t have any neutrophils—that they would get an infection. They would die of the infection before they had a chance for the chemotherapy to have maximum effect. We began to look at regimens where we could try to prevent them from getting the infection. The major focus here was on fungal infections, Candida in particular. That’s the most frequent fungal infection; at least it was at that time. The fluconazole could be taken by mouth and that had very little toxicity, so it was an ideal agent for prophylaxis. The only problem with it was if you used the prophylaxis, then you don’t have anything comparable to use for therapy, so you would have to go to amphotericin or something like that.
Tacey Ann Rosolowski, PhD:
And the problem with amphotericin—was there more toxicity?
Gerald P. Bodey Sr., MD:
That’s got a lot of toxicity.
Tacey Ann Rosolowski, PhD:
Oh, really. What would the effects be? What were the toxic effects?
Gerald P. Bodey Sr., MD:
One of the concerns would be damaging the kidneys. That was probably the biggest side effect, but there were others as well. It wasn’t terribly well tolerated by patients either. It was an effective drug, and it’s still being used, but it’s a drug that has toxicities. Obviously, you’re looking for a drug that’s effective and doesn’t have toxicities. The fluconazole met that.
Recommended Citation
Bodey, Gerald P. MD and Rosolowski, Tacey A. PhD, "Chapter: 03 New Research in the Department of Developmental Therapeutics" (2013). Interview Chapters. 987.
https://openworks.mdanderson.org/mchv_interviewchapters/987
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