M***D
发帖数: 249 | 1 Antipsychotics: A New Hope Against Glioblastoma
Researchers have discovered that FDA-approved antipsychotic drugs possess
tumor-killing activity against the most aggressive form of primary brain
cancer, glioblastoma.
The team of scientists from the University of California, San Diego School
of Medicine, led by principal investigator Clark C. Chen, MD, PhD, used a
technology platform called shRNA to test how each gene in the human genome
contributed to glioblastoma growth.
ShRNA stands for small hairpin or short hairpin RNA, and this type of RNA
sequence makes a tight hairpin turn that can silence target gene expression
by RNA interference. The discovery that led to the shRNA technology won the
Nobel Prize in Physiology/Medicine in 2006.
"ShRNAs are invaluable tools in the study of what genes do. They function
like molecular erasers," said Chen. "We can design these 'erasers' against
every gene in the human genome. These shRNAs can then be packaged into
viruses and introduced into cancer cells. If a gene is required for
glioblastoma growth and the shRNA erases the function of that gene, then the
cancer cell will either stop growing or die."
Chen said that one surprising finding is that many genes required for
glioblastoma growth are also required for dopamine receptor function.
Dopamine is a small molecule that is released by nerve cells and binds to
the dopamine receptor in surrounding nerve cells, enabling cell
communication.
Abnormal dopamine regulation is associated with Parkinson's disease,
schizophrenia, and attention-deficit/hyperactivity disorder. Because of the
importance of dopamine in these diseases, drugs have been developed to
neutralize the effect of dopamine, called dopamine antagonists.
Following clues unveiled by their shRNA study, Chen and his team tested the
effects of dopamine antagonists against glioblastoma and found that these
drugs exert significant antitumor effects both in cultured cells and mouse
models. These effects are synergistic when combined with other anti-
glioblastoma drugs in terms of halting tumor growth.
"The antiglioblastoma effects of these drugs are completely unexpected and
were only uncovered because we carried out an unbiased genetic screen," said
Chen. This study was published online in Oncotarget on March 7, 2014.
"On the clinical front, the finding is important for two reasons," said Bob
Carter, MD, PhD, chairman of UC San Diego, School of Medicine, Division of
Neurosurgery. "First, these drugs are already FDA-cleared for human use in
the treatment of other diseases, so it is possible these drugs may be
repurposed for glioblastoma treatment, thereby bypassing years of
preclinical testing. Second, these drugs have been shown to cross the blood-
brain barrier, a barrier that prevents more than 90% of drugs from entry
into the brain."
Chen is now working with the UC San Diego Moores Cancer Center Neuro-
Oncology team to translate his findings into a clinical trial.
This study is so interesting! | d**o
发帖数: 618 | 2 chagrin - so that means the palliative care has been therapeutic all along? | M***D
发帖数: 249 | 3 After HER2 gene was identified in breast cancer patients, gene targeted
chemotherapy have improved the prognosis of countless patients who suffer
from HER2 positive breast cancer.
Likewise, Dr. Chen's clinical study may identify dopamine receptor gene
targeted chemotherapy such as using antipsychotics to treat patients
suffering from Glioblastoma.
Palliative care is definitely important for terminally ill patients
including Glioblastoma patients, but you have missed the profound or even
life-saving clinical significance of Dr. Chen's study.
【在 d**o 的大作中提到】
: chagrin - so that means the palliative care has been therapeutic all along?
| d**o
发帖数: 618 | 4 Getcha. But I doubt this finding can be as significant as HER2. I mention
palliative care because antipsychotics such as halodol have been used
frequently in palliative care of terminal cancer including glioblastoma. If
antipsychotics really have such a clinical anti-glioblastoma effect,
palliative care should have found this effect long ago.
【在 M***D 的大作中提到】
: After HER2 gene was identified in breast cancer patients, gene targeted
: chemotherapy have improved the prognosis of countless patients who suffer
: from HER2 positive breast cancer.
: Likewise, Dr. Chen's clinical study may identify dopamine receptor gene
: targeted chemotherapy such as using antipsychotics to treat patients
: suffering from Glioblastoma.
: Palliative care is definitely important for terminally ill patients
: including Glioblastoma patients, but you have missed the profound or even
: life-saving clinical significance of Dr. Chen's study.
| M***D
发帖数: 249 | 5 I guess you did not read the article carefully. The 3rd paragraph from the
end of the article:
"The antiglioblastoma effects of these drugs are completely unexpected and
were only uncovered because we carried out an unbiased genetic screen,"
said Chen. This study was published online in Oncotarget on March 7, 2014. | A*******s
发帖数: 9638 | 6 I guess the terminal GBM could not be reversed by Haldol prn. And the most
common sedatives are benzos. Using antipsychotics for GBM is an interesting
finding and would wait for more studies.
If
★ 发自iPhone App: ChineseWeb 8.6
【在 d**o 的大作中提到】
: Getcha. But I doubt this finding can be as significant as HER2. I mention
: palliative care because antipsychotics such as halodol have been used
: frequently in palliative care of terminal cancer including glioblastoma. If
: antipsychotics really have such a clinical anti-glioblastoma effect,
: palliative care should have found this effect long ago.
| n***a
发帖数: 1373 | 7 Cell culture studies and mouse studies are too far away from real life.
expression
【在 M***D 的大作中提到】
: Antipsychotics: A New Hope Against Glioblastoma
: Researchers have discovered that FDA-approved antipsychotic drugs possess
: tumor-killing activity against the most aggressive form of primary brain
: cancer, glioblastoma.
: The team of scientists from the University of California, San Diego School
: of Medicine, led by principal investigator Clark C. Chen, MD, PhD, used a
: technology platform called shRNA to test how each gene in the human genome
: contributed to glioblastoma growth.
: ShRNA stands for small hairpin or short hairpin RNA, and this type of RNA
: sequence makes a tight hairpin turn that can silence target gene expression
| M***D
发帖数: 249 | 8 No, it is NOT "too far away from real life" for antipsychotics. As Dr.
Carter said " these drugs are already FDA-cleared for human use in the
treatment of other diseases, so it is possible these drugs may be repurposed
for glioblastoma treatment, thereby bypassing years of preclinical testing."
【在 n***a 的大作中提到】
: Cell culture studies and mouse studies are too far away from real life.
:
: expression
| n***a
发帖数: 1373 | 9 Hope so.
repurposed
testing."
【在 M***D 的大作中提到】
: No, it is NOT "too far away from real life" for antipsychotics. As Dr.
: Carter said " these drugs are already FDA-cleared for human use in the
: treatment of other diseases, so it is possible these drugs may be repurposed
: for glioblastoma treatment, thereby bypassing years of preclinical testing."
| d**o
发帖数: 618 | 10 Faint, cannot imagine you're so serious about this. Did you read the
original paper? Look at Figure 1F's legend, "cells were incubated with
haloperidol at" 10 uM concentration to show a weak tumoricidal effect with
just P = 0.02. Per wikipedia, the therapeutic serum level of halodol is 4-25
ug/L, and mol mass of halodol is 376 g/mol. Thus this experiment was done
with cells buried in a hadolol concentration that's 10/(25/376) = 150 times
higher than the maximum therapeutic serum level. And of course you know NMS
and EPS of high-dose halodol. So, this is just not going to be a viable
treatment option, period.
repurposed
testing."
【在 M***D 的大作中提到】
: No, it is NOT "too far away from real life" for antipsychotics. As Dr.
: Carter said " these drugs are already FDA-cleared for human use in the
: treatment of other diseases, so it is possible these drugs may be repurposed
: for glioblastoma treatment, thereby bypassing years of preclinical testing."
| | | A*******s
发帖数: 9638 | 11 If it is workable, don't worry about serum concentration. Intrathecal Haldol
will do its trick.
But I agree in vitro is not a same animal as in vivo, just like levodopa
which is toxic in vitro.
★ 发自iPhone App: ChineseWeb 8.6
【在 d**o 的大作中提到】
: Faint, cannot imagine you're so serious about this. Did you read the
: original paper? Look at Figure 1F's legend, "cells were incubated with
: haloperidol at" 10 uM concentration to show a weak tumoricidal effect with
: just P = 0.02. Per wikipedia, the therapeutic serum level of halodol is 4-25
: ug/L, and mol mass of halodol is 376 g/mol. Thus this experiment was done
: with cells buried in a hadolol concentration that's 10/(25/376) = 150 times
: higher than the maximum therapeutic serum level. And of course you know NMS
: and EPS of high-dose halodol. So, this is just not going to be a viable
: treatment option, period.
:
| M***D
发帖数: 249 | 12 Yes, you are right that I am serious about Dr. Chen's study.
I guess you did not have experiences with cell culture studies:
(1) In vitro and in vivo conditions are different and you cannot COPY in
vivo therapeutic Haldol level to in vitro Haldol level.
(2) In vivo Haldol has first pass metabolism, while in vitro cultured cells
do not have it. So the in vivo serum Haldol level will be lower than that in
cultured cells.
(3) In a real patient, there are limited number of dopamine receptors on
neurons responding to Haldol or responding to any other antipsychotics.
While in a cell culture, you can have as many neurons responding to Haldol
as you want. Therefore, no matter how high Haldol used for the in vitro
cultured cells, NO physicians shall treat any real patients with the SAME
dosage of Haldol as that used for in vitro cell culture studies.
25
times
NMS
【在 d**o 的大作中提到】
: Faint, cannot imagine you're so serious about this. Did you read the
: original paper? Look at Figure 1F's legend, "cells were incubated with
: haloperidol at" 10 uM concentration to show a weak tumoricidal effect with
: just P = 0.02. Per wikipedia, the therapeutic serum level of halodol is 4-25
: ug/L, and mol mass of halodol is 376 g/mol. Thus this experiment was done
: with cells buried in a hadolol concentration that's 10/(25/376) = 150 times
: higher than the maximum therapeutic serum level. And of course you know NMS
: and EPS of high-dose halodol. So, this is just not going to be a viable
: treatment option, period.
:
| d**o
发帖数: 618 | 13 You're right that I have no hands-on experience with cell culture, but I
know that I can use peer papers to assess a field that I'm not familiar with
. Look at this open-access paper for example
http://www.biomedcentral.com/content/pdf/1471-2210-9-6.pdf
In this cell culture paper Jiang et al. started with a halodol of 0.2 uM,
which seems standard in this field because the halodol solution was prepared
commercially by Sigma-Aldrich. Then, they used a 10-times higher
concentration of 2 uM only in order to study the dose-dependent effect, and
they had to explain why this is out of the norm - still, that's 5 times
lower than the concentration used in Chen's paper! Not to mention that Jiang
et al.'s findings may suggest that Chen's findings may be an artifact of
the high halodol concentration (i.e. stimulating RNA expression).
Also to dampen your hope that Chen's paper is a harbinger of HER2-like gene-
specific treatment for GBM, let me quote this from Chen's paper:
"We next determined whether DRD2 was overexpressed in glioblastoma specimens
. Relative to tumor-adjacent cerebrum, all glioblastoma specimens showed a 4
-17 fold increase in DRD2 mRNA (Figure 2A) or 2-4 fold enhancement in
protein expression (Figure 2B). We further tested whether DRD2 expression
was associated with any particular molecular subtypes of glioblastoma in The
Cancer Genome Atlas (TCGA), but did not identify any specific association (
Supplemental Figure 1)"
cells
in
【在 M***D 的大作中提到】
: Yes, you are right that I am serious about Dr. Chen's study.
: I guess you did not have experiences with cell culture studies:
: (1) In vitro and in vivo conditions are different and you cannot COPY in
: vivo therapeutic Haldol level to in vitro Haldol level.
: (2) In vivo Haldol has first pass metabolism, while in vitro cultured cells
: do not have it. So the in vivo serum Haldol level will be lower than that in
: cultured cells.
: (3) In a real patient, there are limited number of dopamine receptors on
: neurons responding to Haldol or responding to any other antipsychotics.
: While in a cell culture, you can have as many neurons responding to Haldol
| M***D
发帖数: 249 | 14 I have 10 years of research experience in cell culture study (6 years for my
PhD and 4 years as a post-doctoral research fellow), I hope I can help you
to understand Dr. Chen's study better:
(1) Cell cultures
-Cultured normal cells have limited growth in a petri-dish due to lateral
inhibition, while cultured cancer cells grow much faster comparing to
cultured normal cells. Therefore, you must "pass" the cultured cancer cells
from one petri-dish to 2 petri-dishes more frequently in order to keep the
optimal confluence in a petri-dish. Otherwise, too many cancer cells growing
in one petri-dish may die from deprivation of nutrients.
-There are 16 authors from 5 prestigious universities on Dr. Chen's paper,
and these 16 authors did not agree on a random Haldol concentration at 10 uM
to start the whole research project. In fact, in the paper Methods-Cell
lines and reagents, the authors did cell viability test with Haldol
concentrations at both 10 uM and 20 uM.
-Unless you or anybody else cannot replicate the published data by Dr. Chen'
s study using the exactly same experimental methods, it is not valid to "
suggest that Chen's findings may be an artifact of the high Haldol
concentration".
(2)"all glioblastoma specimens showed a 4-17 fold increase in DRD2 mRNA (
Figure 2A) or 2-4 fold enhancement in protein expression (Figure 2B)"---this
makes DRD2 a great target for gene-targeted chemotherapy because the
differences are between glioblastoma cells and normal cells.
(3) The most convincing and exciting data in Dr. Chen's paper are obtained
with in vivo mouse study. Haldol was administrated by IP or oral lavage (at
10 mg/kg weight). Again if you use the mouse dosage based on weight, an
adult weighs 50 kg will need to take 500 mg Haldol daily. No physicians will
prescribe 500 mg Haldol daily to any patients. Why? Because humans have
much slower metabolism rates comparing to mice. Even for a same patient, his
/her Haldol dosage will need to be decreased as he/she gets older because he
/she will have decreased live and kidney functions, so his/her metabolism
rate will be decreased when he/she gets older.
with
prepared
and
Jiang
【在 d**o 的大作中提到】
: You're right that I have no hands-on experience with cell culture, but I
: know that I can use peer papers to assess a field that I'm not familiar with
: . Look at this open-access paper for example
: http://www.biomedcentral.com/content/pdf/1471-2210-9-6.pdf
: In this cell culture paper Jiang et al. started with a halodol of 0.2 uM,
: which seems standard in this field because the halodol solution was prepared
: commercially by Sigma-Aldrich. Then, they used a 10-times higher
: concentration of 2 uM only in order to study the dose-dependent effect, and
: they had to explain why this is out of the norm - still, that's 5 times
: lower than the concentration used in Chen's paper! Not to mention that Jiang
| w*******7
发帖数: 412 | 15 this research result is really fascinating! | M***D
发帖数: 249 | 16 Yes, it is very interesting! Looking forward to reading new progress from
this research.
【在 w*******7 的大作中提到】
: this research result is really fascinating!
|
|
