Cyclopamine, een plantenextract, blijkt in een studie met muizen de groei van hersentumoren te blokkeren. Nieuwe in vitro studies met menselijke kankercellen bevest

20 juli 2011: ik ben kanker-actueel aan het herzien en heb gezocht naar studies met patienten met cyclopamine. Maar er zijn wel heel studies gedaan bij dieren en laboratoriumstudies maar ik vind niet zo snel studies met patienten. Althans niet onder de naam cyclopamine. Wel als je zoekt onder hedgehog + cyclopamine krijg je een heleboel studies, maar is teveel om hier te plaatsen. En veelal ook zijn die studies beperkt tot dierstudies en laboratorium studies

d.d. 20 september 2003: Opnieuw bevestigen in vitro studies met menselijke kankercellen dat cyclopamine (extract uit Lelietje van Dalen) de groei van kankercellen stopt. Zie dit toegevoegde bericht aan eerder bericht over proeven met muizen. .

Laboratoriumproeven met ook menselijke kankercellen geven hoop dat een plantaardige stof, cyclopamine gehaald uit Lily Corn (Lelietje van Dalen) , de groei van hersentumoren (medulloblastoma ) en alvleesklierkankercellen kan stoppen. Zo meldt Nutraingredients op hun website naar aanleiding van onderzoek hiernaar al in 2002 gedaan in het John Hopkins School of Medicine en nu herhaald in Massachusetts General Hospital en Harvard Medical School. Hieronder staat ook beschreven wat precies het mechanisme voor dit opvallende resultaat is. Voor artsen lijken ons deze twee Engelstalige artikelen van Nature en Nutraingredients voldoende. Voor mensen met hersentumoren lees toch ook informatie over medicinale paddestoelen die in Japan al lang in derde fase studies bewezen hebben een positief effect hebben bij de behandeling van o.a. hersentumoren, maar ook bij andere vormen van kanker.

Bron: Nature-online en Nutraingredients.

A plant extract has been found to inhibit tumour growth in laboratory tests. It could be used to target some of the cancers that are currently most difficult to treat, suggests the research.

Two studies published in the early online edition of Nature show that cyclopamine, a chemical extracted from the corn lily, shrinks tumours both in tests on mice and on human cells in vitro.
The findings back previous research demonstrating cyclopamine’s action against cancer. A study by Dr Philip Beachy and colleagues at the John Hopkins School of Medicine last year found that cyclopamine effectively killed cultured mouse medulloblastoma cells and tumours implanted in animals, as well as medulloblastoma cells extracted from human tumours. Medulloblastoma is an aggressive brain cancer, which affects children, but so far cannot be treated.

The researchers believe that cyclopamine blocks the Hedgehog signalling pathway, known to be critical for the growth and differentiation of cells during embryonic development but also implicated in malignancy of tumour cells if activated later in life.

In the new research Dr Beachy reports that high levels of the Hedgehog protein appear to trigger tumours in a wide range of digestive tract tumours, “including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon”. In tests on mice, cyclopamine blocked this protein and significantly reduced the size of tumours after 12 days of treatment.

In a different study published in the journal, Dr Sarah Thayer and colleagues at Massachusetts General Hospital and Harvard Medical School found that hedgehog signalling may also be an important mediator in pancreatic cancer. Again, cyclopamine induced apoptosis of tumour cells in both in vitro and in vivo tests.

The findings suggest that cyclopamine could be used to treat these types of cancer, although researchers will need to carry out further tests to confirm the role of the hedgehog pathway in human cancer.

There could also be barriers in the form of standardising sufficient quantities of cyclopamine, extracted from the Veratrum californicum, a plant native to the US and poisonous in its natural form.

Source: Nature online, 14 September, doi:10.1038/nature01972; doi:10.1038/nature02009

A chemical isolated from a weed that grows in mountain meadows in the western United States kills the cells of an aggressive brain cancer that affects some children, researchers at John Hopkins university have found.

The compound, cyclopamine, blocks a signalling pathway that appears to be important for the survival of medulloblastoma, a form of cancer for which there is no effective treatment.
In an article published in the 30 August 2002, issue of the journal Science, a research team led by Howard Hughes Medical Institute investigator Philip Beachy reported that cyclopamine effectively killed cultured mouse medulloblastoma cells and tumours implanted in animals, as well as medulloblastoma cells extracted from human tumours.

“It will be difficult to obtain sufficient quantities of cyclopamine, since it must be extracted and purified from the plant source, Veratrum californicum, the corn lily,” said Beachy, who is at The Johns Hopkins University School of Medicine.

“However, we believe that with this study, the evidence is in place to justify an effort to develop a supply so that it can be tested in humans.”

Beachy and his colleagues at Johns Hopkins collaborated with researchers from the Fred Hutchinson Cancer Research Center and the University of Washington/Children’s Hospital in Seattle.

Beachy said there are some parallels between cyclopamine and taxol, a drug used to treat breast cancer drug that was initially in short supply because it had to be isolated from the bark of the Pacific yew tree. However, as taxol proved clinically effective, researchers developed an alternate method of partial synthesis of the compound from a more plentiful precursor in the needles that made the drug available in sufficient supply.

Beachy and his colleagues began to explore whether cyclopamine would be effective against medulloblastoma after studies by several groups, including HHMI investigator Matthew Scott and his colleagues at Stanford University, showed that both animals and humans developed tumours, including medulloblastomas, when the Hedgehog signalling pathway was activated.

The pathway — named for its key regulatory protein Hedgehog — has long been known to be critical for the growth and differentiation of cells during embryonic development. Scott and his colleagues showed that the tumours they studied consisted of cells that had most likely reverted to a highly proliferative embryonic state, due to a mutation that enabled the activation of the Hedgehog pathway.

The earlier studies showed that the Hedgehog pathway was switched on when the function of one of the pathway's key genes, called Patched, was lost because of mutation. The protein produced by Patched normally represses a downstream member of the Hedgehog pathway — a protein called Smoothened. Loss of Patched activates the Smoothened protein, turning on the Hedgehog pathway and leading to malignancy.

Beachy and his colleagues had shown previously that cyclopamine blocks the Hedgehog pathway in mouse embryos by inhibiting the activity of Smoothened. Reasoning that the drug might also prevent activation of the Hedgehog pathway in tumours, the scientists tested cyclopamine's effects on a mouse model developed in Scott's laboratory, in which one copy of the Patched gene had been disrupted.

In these mice, Beachy and his colleagues also removed the gene for p53, a protein that normally triggers the death of cells with damaging mutations. The mice developed medulloblastomas at a young age when expression of the second normal Patched gene was inactivated.

The researchers cultured medulloblastoma cells from the mice and introduced those tumour cells into other mice that had compromised immune systems. “We showed that in these tumour cells we could readily suppress the Hedgehog pathway by treating the tumours with cyclopamine,” said Beachy.

“We next decided to see whether the drug would affect tumours that had already been established in mice by injecting the tumour cells. We were pleased to see that cyclopamine could not only block the Hedgehog pathway, but could also stop the growth of these tumours and even cause them to regress,” he said.

The next logical step, said Beachy, was to determine whether cyclopamine was effective in human medulloblastomas. For these studies, co-author James Olson and colleagues at the Fred Hutchinson Cancer Research Center supplied medulloblastoma cells from patients who had undergone surgery to remove the tumours.

“When we treated dispersed cells from these tumours with cyclopamine, they died very quickly, and in fact, the drug appeared to be killing the cells faster than any drug Jim Olson and his colleagues had yet tested,” said Beachy.

Also promising, said Beachy, was that in the animal studies, the drug produced no discernible side-effects. “Of course, we can't be sure that there are no side-effects at this point, since we can’t ask a mouse how it’s feeling,” said Beachy. “But we saw no obvious adverse effects from the treatment.”

One promising result from the studies of human tumour cells, said Beachy, was that all seven of the human medulloblastom that the scientists tested responded dramatically to cyclopamine. “Genetic studies have shown that only perhaps twenty percent of such sporadic tumours can be assigned to mutations that specifically activate the Hedgehog pathway,” he said. “So, this finding suggests that perhaps activation of the Hedgehog pathway is essential to tumorigenesis, even when it is not specifically switched on by mutation.”

Although Beachy advocates immediate pre-clinical and clinical trials of cyclopamine for medulloblastoma, he cautioned that supply is a critical problem. “Right now, cyclopamine must be purified from the corn lily, and it is unclear how much could be harvested or cultivated,” said Beachy. “Synthesizing cyclopamine might be possible, but it would be very difficult.”

Het plantenextract CYCLOPAMINE blijkt de groei van kwaadaardige tumorcellen van het centrale zenuwstelsel - hersentumoren dus - tegen te gaan. Aldus onderzoekers aan de universiteit van het John Hopkins Medisch Centrum. Het gaat om tumoren - medulloblastomen - die zich nestelen bij de kleine hersenen en die vooral bij KINDEREN voorkomen.

Het onderhavige onderzoek is uitgevoerd bij muizen ingespoten met menselijke hersentumoren op basis van (het extract van) de plant Veratrum Californium. Zoals uit de naam blijkt, komt deze plant voor in het Westen van de VS en lijkt op het Lelietje-van-dalen.

30/08/02 - A chemical isolated from a weed that grows in mountain meadows in the western United States kills the cells of an aggressive brain cancer that affects some children, researchers at John Hopkins university have found.

The compound, cyclopamine, blocks a signalling pathway that appears to be important for the survival of medulloblastoma, a form of cancer for which there is no effective treatment.
In an article published in the 30 August 2002, issue of the journal Science, a research team led by Howard Hughes Medical Institute investigator Philip Beachy reported that cyclopamine effectively killed cultured mouse medulloblastoma cells and tumours implanted in animals, as well as medulloblastoma cells extracted from human tumours.

"It will be difficult to obtain sufficient quantities of cyclopamine, since it must be extracted and purified from the plant source, Veratrum californicum, the corn lily," said Beachy, who is at The Johns Hopkins University School of Medicine.

"However, we believe that with this study, the evidence is in place to justify an effort to develop a supply so that it can be tested in humans."

Beachy and his colleagues at Johns Hopkins collaborated with researchers from the Fred Hutchinson Cancer Research Center and the University of Washington/Children’s Hospital in Seattle.

Beachy said there are some parallels between cyclopamine and taxol, a drug used to treat breast cancer drug that was initially in short supply because it had to be isolated from the bark of the Pacific yew tree. However, as taxol proved clinically effective, researchers developed an alternate method of partial synthesis of the compound from a more plentiful precursor in the needles that made the drug available in sufficient supply.

Beachy and his colleagues began to explore whether cyclopamine would be effective against medulloblastoma after studies by several groups, including HHMI investigator Matthew Scott and his colleagues at Stanford University, showed that both animals and humans developed tumours, including medulloblastomas, when the Hedgehog signalling pathway was activated.

The pathway - named for its key regulatory protein Hedgehog - has long been known to be critical for the growth and differentiation of cells during embryonic development. Scott and his colleagues showed that the tumours they studied consisted of cells that had most likely reverted to a highly proliferative embryonic state, due to a mutation that enabled the activation of the Hedgehog pathway.

The earlier studies showed that the Hedgehog pathway was switched on when the function of one of the pathway's key genes, called Patched, was lost because of mutation. The protein produced by Patched normally represses a downstream member of the Hedgehog pathway - a protein called Smoothened. Loss of Patched activates the Smoothened protein, turning on the Hedgehog pathway and leading to malignancy.

Beachy and his colleagues had shown previously that cyclopamine blocks the Hedgehog pathway in mouse embryos by inhibiting the activity of Smoothened. Reasoning that the drug might also prevent activation of the Hedgehog pathway in tumours, the scientists tested cyclopamine's effects on a mouse model developed in Scott's laboratory, in which one copy of the Patched gene had been disrupted.

In these mice, Beachy and his colleagues also removed the gene for p53, a protein that normally triggers the death of cells with damaging mutations. The mice developed medulloblastomas at a young age when expression of the second normal Patched gene was inactivated.

The researchers cultured medulloblastoma cells from the mice and introduced those tumour cells into other mice that had compromised immune systems. "We showed that in these tumour cells we could readily suppress the Hedgehog pathway by treating the tumours with cyclopamine," said Beachy.

"We next decided to see whether the drug would affect tumours that had already been established in mice by injecting the tumour cells. We were pleased to see that cyclopamine could not only block the Hedgehog pathway, but could also stop the growth of these tumours and even cause them to regress," he said.

The next logical step, said Beachy, was to determine whether cyclopamine was effective in human medulloblastomas. For these studies, co-author James Olson and colleagues at the Fred Hutchinson Cancer Research Center supplied medulloblastoma cells from patients who had undergone surgery to remove the tumours.

"When we treated dispersed cells from these tumours with cyclopamine, they died very quickly, and in fact, the drug appeared to be killing the cells faster than any drug Jim Olson and his colleagues had yet tested," said Beachy.

Also promising, said Beachy, was that in the animal studies, the drug produced no discernible side-effects. "Of course, we can't be sure that there are no side-effects at this point, since we can’t ask a mouse how it’s feeling," said Beachy. "But we saw no obvious adverse effects from the treatment."

One promising result from the studies of human tumour cells, said Beachy, was that all seven of the human medulloblastom that the scientists tested responded dramatically to cyclopamine. "Genetic studies have shown that only perhaps twenty percent of such sporadic tumours can be assigned to mutations that specifically activate the Hedgehog pathway," he said. "So, this finding suggests that perhaps activation of the Hedgehog pathway is essential to tumorigenesis, even when it is not specifically switched on by mutation."

Although Beachy advocates immediate pre-clinical and clinical trials of cyclopamine for medulloblastoma, he cautioned that supply is a critical problem. "Right now, cyclopamine must be purified from the corn lily, and it is unclear how much could be harvested or cultivated," said Beachy. "Synthesizing cyclopamine might be possible, but it would be very difficult."