This concludes the Feast of Reason, and the last speaker is reminiscent of the last man to finish a marathon race. Two hours ago, the race is finished.

The winner is known, it's also known to the last speaker, but he's determined to finish anyway. I'll try to remember that brevity is the soul of wit. Professor Sund, ladies and gentlemen, the picturesque concept of jobber kugel was introduced

by Paul Ehrlich to describe the effect of aromatics bearing bivalent arsenic on parasites. Now we shall attempt a pharmacologic dissection of adrenal cortex. I believe that techniques rule science, that seated at your desk you have no chance.

The maturity of any branch of science depends upon the available techniques. Cancer research is not done very well because the techniques have been rather clumsy. We wanted a rapid and simple method to induce cancer.

In every experimental animal, we want to do it quickly and without any work. We decided we would devote a few months in search of one, the most potent of the polycyclic aromatic carcinogenic hydrocarbons.

Second, we would look for the most susceptible tissue of living creatures. And third, we would combine A and B and determine the maximum amount tolerable by the animal. I realize that the emotional tension is terrible, so I'll quickly tell what the answers

to these questions are. The most potent of the polycyclic aromatic hydrocarbons is 7-12 dimethyl benzanthracene. In English, this is 7-12 dimethyl benzanthracene.

Let us abbreviate this and it's 7-12 dim-ba. As you know, this has a Chinese meaning and it is this.

The sinologists in the audience recognize right away that this is dim or fires. This is ba or eight. When you give a dose of dim-ba, you light eight fires. Namely, you elicit eight cancers.

How is this done? One gives a dose to a young adult rat by mouth, 30 milligrams dissolved in oil by stomach tube and cancer is underway.

The cancer starts within one hour and this is fine. It's slightly clumsy, slightly clumsy to give a feeding. This is cancer induced by a single meal of the rat, but it's a little clumsy.

So what one does now, this is the 1968 model. The 1969 model is this. One dissolves the hydrocarbon in oil. One homogenizes the oil in water and then one injects intravenously.

Therefore, at a given instant of time, at a precisely known instant of time, the cancer has started and it's known that the cancer is underway within 60 minutes because if

you take the most sensitive tissue and transplant it to another animal, the animal developed cancer. Now, the most sensitive tissue of the known in biology is mammary gland of young adult rats and this is the most sensitive to two things, polycyclic aromatic

hydrocarbons and also to radiation. This is still a fourth way that one can represent, deemed by the methods of Kekulé. Now, science is people.

This is Werner Bachmann, 1901 to 1951, a creative chemist who spent his professional life at the University of Michigan studying one thing, namely free radicals.

He synthesized first, Dean Bach. We were busy and happy with the new discovery, producing cancer in every animal. It was what you call instant cancer. It was second, do it yourself.

It was third, cancer research without tears since it was kinder spiel and without statisticians since it was 100% and so this was quite good. But scientists in the lab is this.

All kinds of wonderful things go on in the laboratory that a scientist does not see. I think that a scientific man in the laboratory is rather good at devising experiments and not very good at observing that which is going on around him.

This is not Venus de Milo, this is a rat which 50 days ago was received a massive intravenous injection of Dean Bach, a large tolerable dose we call pustose because at

a precise second of time it is introduced into the blood and 50 days ago this animal was injected and here one sees four of the eight fires which are elicited.

And we studied this and the thing about cancer is to cure it, right? We were doing that and looking at these things but one day we found these animals had very large adrenals which were very hard and we thought well this is great.

Now this is adrenal cancer but we made a section of the adrenal and found that the animals which had received Dean Bach, the middle of the adrenal had turned into stone. What was the incidence of that?

100%. And how long had it been going on? Since the time of the pustose and it had taken us three months to observe this. So we thought we better study the invariable effect, the selective destruction, the

Haber-Kugel of Dean Bach on middle layer of adrenal cortex. Bitter dust next to it. The adrenal gland from a biochemical standpoint consists of three layers, the outer layer glomerulosa, the middle layer fasciculata reticularis and the inner is medulla.

Now these are all very long and hard names and the mind is not a bottomless pit. So we remember these things in the following way. One of the great steroid chemists of the age, Guy F. Marion, we will give him Guy

Frederick Marion, we will give him an additional name which he does not have of Richard. Now he becomes Guy Frederick Richard Marion. Let us kill Frederick and Richard and then Guy Marion will stay alive. So that's what we do.

Bitter dust next to it. This is adrenal cortex of the rat and blood enters the outer layer of glomerulosa and then it starts its slow descent on the chromatographic columns to the medulla.

Middle layer is this great area. This is what is destroyed by Dean Bach. Middle layer then consists of the chromatographic columns that carry the blood and of hormone

secretory cells. And when you destroy either one or the other and you can destroy either the chromatographic columns or the hormone secretory cells, when you destroy one or the other then both die. So and that gives place to adrenal apoplexy.

This is a great vivid display of nature reminiscent of red lights in the dark. The chromatographic columns are lined with sinusoidal endothelium which can phagocyte particulate matter. Bitter dust next to it.

This is a demonstration of the chromatographic, the lining of the chromatographic columns. Thorium dioxide has been injected and it has been ingested and these are little mirrors which reflect the light and show that this is sinusoidal endothelium which

can phagocytize particles. Bitter dust next to it. Here is the effect of adrenal apoplexy. Three days ago there is injection of Dean Bach.

And for 24 hours nothing happens and then at 30 hours the adrenal gland bleeds. Here is the control. Bitter dust next to it.

Here we see the three layers of adrenal. The outer layer with the anastomosing capillaries where aldosterone is formed. Here is one of the chromatographic columns which is still open. The others have died and here is the adrenal apoplexy which is reminiscent of red lights

in the dark. Bitter dust next to it. Histology. The outer layer is perfect and undamaged. The medulla is perfect and undamaged. The middle layer is killed by Zauberkugel, namely Bitter dust next to it.

And here on the ninth day you see adrenal medulla and you see here the adrenal gland has turned into stone and this is a permanent mark.

This stone in the middle of the adrenal calcification of the necrotic tissue. This is the necrotic tissue. These are adrenal glands from six rats. Each one received a pulse dose nine days ago and this stone means X days ago

this animal was exposed to DIMBA or one of its congeners. Now this susceptibility of the adrenal gland Bitter dust next to it is ACTH dependent.

It can be produced by a meal, namely 30 milligrams of CBN-12 or by injection. The young animal can tolerate more of it than the old animal. The young animal at age 25 days received 30 milligrams and at 45 days 30 milligrams.

At 25 days no adrenal apoplexy. At 45 days 10 out of 10. But the hormone that it depends on is corticotrophin. You start at 21 days in one of these animals and give corticotrophin for four days

and then a single feeding of the corticolitic agent and then you have adrenal apoplexy. Bitter dust next to it. So we've been interested in this thing, this observation, which is really it's kinder spiel to do.

All you need to know is can you tell the difference between red and white? If you're color blind, select another experiment. Here we have the base pairs. This is a wonderful thing. This is steric relationship.

This is thymine and adenine and one makes a little box to surround the base pairs. Bitter dust next to. In this little box fits Sieben-Schwauf-de-Matil-Benzon-Thresain.

It has the same steric size as the base pairs, guanine-cytosine or adenine-thymine. So this little box is a simple way to judge steric relationships.

Bitter dust next to. Here again is the Pandora box constructed to hold the base pairs and in this fits well cortisol. So here we see three things that fit in this box.

The base pairs, the most powerful polycyclic aromatic hydrocarbons and the active sex hormones and corticotrophic hormones. Bitter dust next to. Now this is the dimethylbenzon-thresain and Boylan found that it readily undergoes hydroxylation.

Now this very powerful carcinogen differs from most polycyclic aromatic hydrocarbons.

They undergo hydroxylation in the ring structure but Sieben-Schwauf undergoes hydroxylation in the methyl groups preferentially to form 7-hydroxymethyl-12-methylbenzon-thresain or 12-hydroxymethyl-7-methylbenzon-thresain or 7-12-dihydroxybenzon-thresain.

Only this one is corticolytic. These do not destroy the adrenal cortex of the rat. Bitter dust next to.

In this region, if you want to get ahead, sometimes what you do is twist the formula around and that's what has been done here. This is 7-hydroxymethyl-12-methylbenzon-thresain related to cortisol and you can see there is a considerable similarity.

This is buckled and this is flat. This is not carcinogenic. This is a weak carcinogen. Without hydroxymethyl, it is the strongest one that is known.

Now we know the molecular structure of the corticolytic hydrocarbons. They are derivatives of benzanthosine. It is obligatory that a methyl group be present at position 12. It is also obligatory that an additional alkyl or hydroxy alkyl group be present at position 7.

This is a bifunctional effect of one of the functions, namely that at position 12 being required to be a methyl group with an ethyl group escapenous.

This must be methyl. Here you have a considerable leeway. For example, with the following groups, these derivatives are synthesized in our laboratory. With a methyl group, 7-12-dimba.

This is corticolytic. 7-hydroxymethyl-12-methyl. Corticolytic. 7-formyl-12-methyl. We'll assume in the next minute that all of the groups are derivatives of 12-methylbenzon-thresain.

1-hydroxyethyl. 2-hydroxyethyl. N-propyl. 1-hydroxy-N-propyl. So the corticolytic agent which selectively destroys, massively destroys adrenal cortex consists of derivatives of benzanthracene.

12-methylbenzon-thresain with an oxygen function in this region, either synthesized or derived through metabolism in the animal.

Fiat lux. It looks fiat. I don't mean that in an irreverent way.

So the party line was this. They said this damages adrenal cortex because of similarity to cortisol and corticosterone.

A very clever man now entered the picture and his name was Professor Currie. Professor Currie administered to animals in advance an adrenal cortical, an inhibitor of hydroxylation.

11-beta hydroxylation. 17-alpha hydroxylation. This is metapyrone. If one gives in advance metapyrone and then dimba, escapenex, there is no adrenal apoplexy.

So inhibitors of adrenal hydroxylation inhibit the damaging effect of this compound. It is now known that there are many compounds which can't protect the adrenal cortex. These must be given in advance.

The system is this. Day minus one or day minus two, one gives the protector. For example, the metapyrone of Professor Alistair Currie of Aberdeen University. On day zero, one gives the challenger, namely Sieben-Schwalt intravenously, the homogenized hydrocarbon.

On day three, you harvest the adrenal glands, homogenize, and determine how much hemoglobin is present by spectrophotometer. And this is control. This is water clear. This is adrenal gland from an animal treated with Sieben-Schwalt.

And these are protected. One with fluorine and one aminocrycine. Aminocrycine is a strong carcinogen which can protect. These are aromatic compounds and so is metapyrone.

And these aromatic compounds induce so-called drug metabolizing enzymes in liver. So this leads to destruction of, extensive destruction of the corticolytic agent.

Here I demonstrated how you could protect adrenal cortex by aromatics of the type of metapyrone. Here is protection of life.

This compound, 712-DMBA, is a DNA reagent. It has unusual properties, but it is a DNA reagent of the same sort as actinomycin.

A fatal dose is given intravenously to this animal. How does it feel like when DNA synthesis stops? No one knows. No one can tell that, but this is how it looks like in a rat. This is 15 hours later. This animal has no uptake, no incorporation of tritiated thymidine into DNA.

There is tremendous stimulation of RNA synthesis. There is profound stimulation of protein synthesis.

This is dying animal, but he dies with all flags flying with RNA synthesis and protein synthesis as never before. But here is sister, which is protected. Protected with what? Protected with the same thing, 712-DMBA.

In other words, 24 hours previously, one milligram is injected intravenously in tail vein. And at zero hour, a fatal dose, 20 milligrams of DMBA, is given to each. And this one survives, later develops cancer naturally.

But this one dies. This case then shows that an animal which received 21 milligrams lived and 20 milligrams died of the same compound. Next, please. This is hydrocarbon.

These are not my initials specifically. Hydrocarbon protection against cancer. This is memory cancer. Breast cancer is induced in every animal. Cancer research without tears and without statisticians, 74 out of 74. Therefore, if one animal in a group of 10 misses and does not develop cancer, this is suspicious.

If three or six animals fail to develop cancer, then this is certain to be protected. So here you protect the animal with these compounds.

So this is prophylaxis of cancer. Now, many people work on this because it's simple and it's a very profound effect. And we think it's a noble effect because one tries to do something for cancer people.

And Celia says the following, look, if adrenal cortical inhibitor of hydroxylation will do it, let us try for no reason at all. Let us try another adrenal inhibitor that's not, namely, this is spironolactone.

This blocks 11 beta hydroxylation. This blocks the synthesis of aldosterone. This also blocks the effect of dimethyl benzanthosine on adrenal cortex.

Question, will this inhibitor of 11 beta hydroxylation prevent cancer? Three years from now we know, but the race is on and time is passing. And thank you very much.