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Working on a gastrin antagonist


Increasing incidences of oesophageal adenocarcinoma?
James Black Scientist
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When I did my medicine during the war, cancer of the oesophagus was not common but recognised, and it was cancer of the upper part of the oesophagus. And the oesophagus is lined by what's called stratified squamous epithelium – multi-layers of cells on the base membrane, like skin – and so cancers of that are... are called squamous cell cancers. So squamous cell cancers of the oesophagus were recognised, not awfully common; then there has been now... epidemiologically it's quite hard to date when it started, but there is no doubt, everybody is agreed, that the incidence of a new type of oesophageal cancer – adenocarcinoma of the lower end of the oesophagus – is going up and up and up and up. It's the fastest growing incidence of tumours in the West. Everybody's agreed about that. What no one's agreed about is why. But it does look as though the only known predisposing fact...

[Q] This is independent of gender or racial origin?

Mainly more in men than women. It... it's well recognised in the West, but we now know the Chinese suffer badly from it as well; the Japanese not so much. So there are... there are differences, as there all... are in all disease incidences, and I... I daresay it's got a lot to do with our eating habits as well but, anyway, we'll come to that. The point is that something else had been discovered as increasing, and this is associated with reflux. Where the oesophagus joins the stomach, the acid from the stomach refluxes into the oesophagus and gradually, in some patients, the... changes in the epithelium occur. So, instead of being stratified squamous it becomes simple columna with mucus secreting cells, and this is called Barrett's oesophagus, and it begins off just as a... what's called a dysplasia. I beg your pardon, a metaplasia: changes in the cell type. But, as time goes on, this becomes dysplastic and looks more and more cancer-like, and there are those people who believe that, in fact, it is the precursor for the undoubted increase in adenocarcinoma. So, it's an adenocarcinoma coming from this Barrett's oesophagus. Now, it's amazing how it's hard to pin things down. There has been, since about 1980, a huge increase in the incidence of adenocarcinoma. There has been an increase in incidents of Barrett's, or has there? There has been an increase in proceed... of... or the diagnoses by endoscopy so we know there has been a huge increase in the number endoscopies, there has been an increase in the recognition of Barrett's oesophagus, there has been an undoubted increase in cancer. The question is: are they related? Now, people at the Mayo, for example, argue that the increased incidence of endoscopy just means that you're recognising something which... whose frequency hadn't changed because they're doing more of them. And then the people like me say, 'But wait a minute, why were they being endoscoped other than they had a complaint?' So... because the technology had... was known before the 1980s. So, I argue that the increase in incidence is real. The increase in endoscopies is because there's been more demand for it because more symptoms are coming from reflux disease. So, this is the situation today: that reflux disease is the main grounds for prescribing proton pump inhibitors. Proton pump inhibitors produce huge increases in the level of gastrin in blood when you eat. Gastrin is a growth factor to ECL cells, but it... it's also a growth factor to any cells that express gastrin receptors. Now, there's some evidence that when the epithelium changes associated with chronic reflux from stratified squamous to columna, that the columna cells now express gastrin receptors, and so some people believed that Barrett's is being driven by the hypergastrinaemia, induced by the drug which is giving relief. And again, it's quite hard to tack down, but there's no universal agreement about whether or not when you take someone who's refluxing who's got Barrett's, if you stop the acid, you stop the symptoms, there's no longer any pain, the patients feel fine, does the Barrett's heal? Now there are those of us who believe that it doesn't; that the surface of the lesion epithelialises over and looks a bit more normal, but the underlying lesion stays there. So, that was the situation in 1988. So, having had this long love affair with histamine and gastrin, that's the first project we took on here, and now I'm self-conscious about it; I want to make a gastrin antagonist by starting with gastrin.

The late Scottish pharmacologist Sir James W Black (1924-2010) revolutionised medical treatment of hypertension and angina with his invention of propranolol, the first ever beta blocker. This and his synthesis of cimetidine, used for the treatment of peptic ulcers, earned him the Nobel Prize in Physiology or Medicine in 1988.

Listeners: William Duncan

After graduating with a BSc Bill Duncan went on to gain a PhD from Edinburgh University in 1956. He joined the Pharmaceuticals Division of ICI where he contributed to the development of a number of drugs. In 1958, he started a collaboration with Jim Black working on beta blockers and left ICI with him in 1963 to join the Research Institute of Smith Kline & French as Head of Biochemistry. He collaborated closely with Black on the H2 antagonist programme and this work continued when, in 1968, Duncan was appointed the Director of the Research Institute. In 1979, he moved back to ICI as Deputy Chairman (Technical), a post he occupied until 1986 when he became Chairman and CEO of Coopers Animal Health. He ‘retired’ in 1989 but his retirement was short-lived and he held a number of directorships in venture capital backed companies. One of his part-time activities was membership of the Bioscience Advisory Board of Johnson and Johnson who asked him to become Chairman of the Pharmaceutical Research Institute of Johnson and Johnson in New Jersey. For personal reasons he returned to the UK in 1999, but was retained by Johnson and Johnson until 2006 in a number of senior position in R&D working from the UK. From 1999 to 2007 he was a non-executive director of the James Black Foundation. He is now fully retired.

Tags: Mayo Clinic, 1988

Duration: 6 minutes, 12 seconds

Date story recorded: August 2006

Date story went live: 02 June 2008