Regulation of prostate cancer cell growth and PSA expression by angiotensin II receptor blocker

Ishiguro H, Ishiguro Y, Kubota Y, Uemura H.
Regulation of prostate cancer cell growth and PSA expression by
angiotensin II receptor blocker with peroxisome proliferator-activated
receptor gamma ligand like action.
Prostate. 2007 Apr 17; [Epub ahead of print]
PMID: 17440964 [PubMed - as supplied by publisher]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17440964>

"Department of Urology, Yokohama City University Graduate
School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan.

BACKGROUND: We previously reported that angiotensin II (AII)
activated the proliferation of prostate cancer cells, and its
antagonist, an AII receptor type 1 (AT1R) blocker (ARB),
inhibited the proliferation of prostate cancer in vitro and in
vivo. In the present study, we investigated whether
telmisartan, an ARB, has a unique feature as a peroxisome
proliferator-activated receptor gamma (PPARgamma) ligand, and
its suppressive potential on prostate cancer cells. METHODS:
Cell count or MTT assay were carried out for growth suppression
of prostate cancer cells. Phosphorylation of mitogen-activated
protein kinase (MAPK), specific expression of prostate specific
antigen (PSA) and AT1R were investigated by western blot. To
confirm the PPARgamma activity of ARBs, luciferase assay using
PSA promoter and PPARgamma response elements (PPRE) plasmids
was performed. RESULTS: The results showed that cell
proliferation and signal transduction were inhibited by
telmisartan treatment. Also, inhibition of PSA expression by
telmisartan was confirmed by western blot and luciferase assay,
indicating that an ARB acted in a similar way such as an anti-
androgenic agent in prostate cancer cells. CONCLUSION: The
present study showed ARBs, especially those possessing a
PPARgamma ligand-like structure, have a potential antagonistic
effect on androgen-dependent and -independent prostate cancer.
Prostate (c) 2007 Wiley-Liss, Inc."


--
Matti Narkia

Again Matti...What is significant here? Mice are so far away from
humans in terms of disease treatment, and petri dishes and mutated
cell lines are light years even farther away. I would guess by now
there are close to a thousand substances that down- or up-regulate the
various factors involved in prostatic cell mutation. What makes
Telmisartan more important than any of the other 999 factors. Why do
you see this paper as significant. Each day there are well over
100-200 articles published that relate to PCa. Do you feel this paper
was one of the top few?..ron

On 19 Apr 2007 13:42:29 -0700, ron <oitbso@yahoo . com > wrote:

>Again Matti...What is significant here? Mice are so far away from
>humans in terms of disease treatment, and petri dishes and mutated
>cell lines are light years even farther away. I would guess by now
>there are close to a thousand substances that down- or up-regulate the
>various factors involved in prostatic cell mutation. What makes
>Telmisartan more important than any of the other 999 factors. Why do
>you see this paper as significant. Each day there are well over
>100-200 articles published that relate to PCa. Do you feel this paper
>was one of the top few?..ron

Ron, remember that these are science groups, not support groups.
Things posted here don't need to be applicable as treatment today. For
me it is highly interesting, that angiotensin II receptor blockers in
general, not telmisartan particularly, can have an effect on prostate
cancer. I confess that I didn't know that, it was important news to
me, that angiotensin II receptor blockers can also have that effect.
This news may have some relevance already now, perhaps not so much in
the treatment of prostate cancer, which hopefully I do not yet have,
but for example in choosing blood pressure medication. Then
angiotensin II receptor blockers may get a higher priority in BP drug
selection, if they may also have some potential in preventing prostate
cancer. I believe that knowledege is power, although today there is so
much information and studies available, that we need some kind of
mental and technology-based filters to get us only what we need. This
study passed my filters for the reasons I mentioned. Your perspective
may be different.

Your meta-views about the posting treshold have of course their own
interest, but I'd rather discuss the the content of the messages, if
it raises interest. After all, irrelevant or uninteresting on-topic
messages can be easily skipped withouth deep and thorough
meta-discussion. However, I don't want to start meta-meta-discussion.
:-)

Best wishes and good health.



--
Matti Narkia

On Fri, 20 Apr 2007 00:23:40 +0300, Matti Narkia <mna@mbnet.fi> wrote:

>On 19 Apr 2007 13:42:29 -0700, ron <oitbso@yahoo . com > wrote:
>
>>Again Matti...What is significant here? Mice are so far away from
>>humans in terms of disease treatment, and petri dishes and mutated
>>cell lines are light years even farther away. I would guess by now
>>there are close to a thousand substances that down- or up-regulate the
>>various factors involved in prostatic cell mutation. What makes
>>Telmisartan more important than any of the other 999 factors. Why do
>>you see this paper as significant. Each day there are well over
>>100-200 articles published that relate to PCa. Do you feel this paper
>>was one of the top few?..ron
>
>Ron, remember that these are science groups, not support groups.
>Things posted here don't need to be applicable as treatment today. For
>me it is highly interesting, that angiotensin II receptor blockers in
>general, not telmisartan particularly, can have an effect on prostate
>cancer. I confess that I didn't know that, it was important news to
>me, that angiotensin II receptor blockers can also have that effect.
>This news may have some relevance already now, perhaps not so much in
>the treatment of prostate cancer, which hopefully I do not yet have,
>but for example in choosing blood pressure medication. Then
>angiotensin II receptor blockers may get a higher priority in BP drug
>selection, if they may also have some potential in preventing prostate
>cancer.

I also managed to find this pilot study with humans, so we can forget
mice for a moment:

Uemura H, Hasumi H, Kawahara T, Sugiura S, Miyoshi Y, Nakaigawa N,
Teranishi J, Noguchi K, Ishiguro H, Kubota Y.
Pilot study of angiotensin II receptor blocker in advanced
hormone-refractory prostate cancer.
Int J Clin Oncol. 2005 Dec;10(6):405-10.
PMID: 16369744 [PubMed - indexed for MEDLINE]
< * w w w .springerlink . com /content/ph110x618673p073/>
< * w w w .springerlink . com /content/ph110x618673p073/fulltext.pdf>
(full text PDF file)

"BACKGROUND: We previously demonstrated that an angiotensin II
receptor blocker (ARB) had the potential to inhibit cell
proliferation of prostate cancer. In this study, we examined
whether an ARB could elicit an antiproliferative effect on
hormone-refractory prostate cancer, clinically. METHODS:
Twenty-three patients with advanced hormone-refractory prostate
cancer who had already received secondary hormonal therapy
using dexamethasone, and who were no longer receiving
conventional therapy, were enrolled. All of the patients
received candesartan 8 mg once daily per os and,
simultaneously, androgen ablation. Change in prostate-specific
antigen (PSA) was determined as the primary endpoint. The
secondary end-point was change in performance status (PS). To
investigate angiotensin II type 1 (AT1) receptor expression in
prostate cancer tissue, real-time quantitative reverse
transcriptase-polymerase chain reaction (RT-PCR) was performed,
using specimens, from untreated patients with prostate cancer.
RESULTS: Eight patients (34.8%) showed responsive PSA changes;
six showed a decrease immediately after starting administration
and two showed a stable level of PSA. Six men with a PSA
decline of more than 50% showed an improvement in PS. The mean
time to PSA progression (TTPP) in responders was 8.3 months
(range, 1-24 months). Half of the patients showed stable or
improved PS during treatment. With regard to toxic effects,
only one patient showed hypotension during treatment. The RT-
PCR showed that AT1 receptor expression in well-differentiated
adenocarcinoma was higher than that in poorly differentiated
adenocarcinoma. CONCLUSION: These data showed that an ARB had
potential biological effects on prostate cancer, suggesting the
usefulness of the cytostatic activity of such agents on
recurrent prostate cancer."


The qustion which immediately comes to mind is: Do also ACE-inhibitors
help in preventing prostate cancer or any cancer for that matter? This
question was perhaps first asked in the article:

Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL,
Meredith PA, Murray LS, Reid JL, Robertson JW.
Do inhibitors of angiotensin-I-converting enzyme protect against risk
of cancer?
Lancet. 1998 Jul 18;352(9123):179-84.
PMID: 9683206 [PubMed - indexed for MEDLINE]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9683206>

"BACKGROUND: Previous studies have reported an increased risk
of cancer with calcium-channel blockers in man. Other work in
animals suggests that inhibitors of angiotensin-I-converting
enzyme (ACE) protect against cancer. We aimed to assess the
risk of cancer in hypertensive patients receiving ACE
inhibitors or other antihypertensive drugs. METHODS: Our
retrospective cohort study was based on the records of 5207
patients who attended the Glasgow Blood Pressure Clinic between
Jan 1, 1980, and Dec 31, 1995. The patients' records are linked
with the Registrar General Scotland and the West of Scotland
Cancer Registry. FINDINGS: Compared with the West of Scotland
controls, the relative risks of incident and fatal cancer among
the 1559 patients receiving ACE inhibitors were 0.72 (95% CI
0.55-0.92) and 0.65 (0.44-0.93). Among the 3648 patients
receiving antihypertensive drugs other than ACE inhibitors
(calcium-channel blockers 1416, diuretics 2099, beta-blockers
2681), the corresponding relative risks were 110 (0.97-1.22)
and 1.03 (0.87-1.20). The relative risk of cancer was lowest in
women on ACE inhibitors: 0.63 (0.41-0.93) for incident cancer;
0.48 (0.23-0.88) for fatal cancer; and 0.37 (0.12-0.87) for
female-specific cancers. The reduced relative risk of cancer in
patients on ACE inhibitors was greatest with follow-up of
longer than 3 years. Calcium-channel blockers, diuretics, and
beta-blockers had no apparent effect on risk of cancer.
INTERPRETATION: Long-term use of ACE inhibitors may protect
against cancer. The status of this finding is more that of
hypothesis generation than of hypothesis testing; randomised
controlled trials are needed."

The study's

Ronquist G, Rodriguez LA, Ruigomez A, Johansson S, Wallander MA,
Frithz G, Svardsudd K.
Association between captopril, other antihypertensive drugs and risk
of prostate cancer.
Prostate. 2004 Jan 1;58(1):50-6.
PMID: 14673952 [PubMed - indexed for MEDLINE]
DOI: 10.1002/pros.10294
< * w w w 3.interscience.wiley . com /cgi-bin/abstract/106561911/ABSTRACT?CRETRY=1&SRETRY=0>
< * w w w 3.interscience.wiley . com /cgi-bin/fulltext/106561911/PDFSTART>

answer to the question is maybe. ACE-inhibitor captopril use was
associated with a relative risk of 0.7 (95% CI: 0.4-1.2) for prostate
cancer:

"... We found that users of captopril had a relative risk of
0.7 (95% CI: 0.4-1.2) to develope prostate cancer. None of the
other studied individual ACE-inhibitors shared a similar effect
with the one observed for captopril. CONCLUSIONS: No clear
association was apparent between the use of antihypertensive
drugs and prostate cancer. However, specific focus on users of
captopril showed a lower risk of subsequent prostate cancer.
Further research is needed to explore this association. ..."

As we can see from 95% confidence limits, the result was not
statistically significant though, but perhaps study did not enough
power for that.

But this mice study shows promotion of immunogenic tumors by captopril
in mice:

P. J. Wysocki, E. P. Kwiatkowska, U. Kazimierczak, W. Suchorska, D. W.
Kowalczyk, and A. Mackiewicz
Captopril, an Angiotensin-Converting Enzyme Inhibitor, Promotes Growth
of Immunogenic Tumors in Mice.
Clin. Cancer Res., July 1, 2006; 12(13): 4095 - 4102.
< * clincancerres.aacrjournals.org/cgi/content/abstract/12/13/4095>


There seems to be quite a many studies about this very interesting
topic. I scratched the surface a bit and found these studies:

Uemura H, Hasumi H, Ishiguro H, Teranishi J, Miyoshi Y, Kubota Y.
Renin-angiotensin system is an important factor in hormone refractory
prostate cancer.
Prostate. 2006 Jun 1;66(8):822-30.
PMID: 16482568 [PubMed - indexed for MEDLINE]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16482568>

"BACKGROUND: The aim of this study was to perform a
comprehensive evaluation of the renin-angiotensin system (RAS)
in prostate cancer. METHODS: We investigated the expression of
RAS components in prostate cancer cells treated with hormonal
agents. Real-time PCR data showed the expression of the AT1
receptor, angiotensin I converting enzyme (ACE), and
angiotensin I/II (Ang-I/II) precursor in all 87 prostate tissue
samples. RESULTS: Expression of these genes in hormone
refractory prostate cancer (HRPC) was significantly higher than
that in normal prostate tissue and untreated prostate cancer
tissue. Western blot showed that protein expression of the AT1
receptor and Ang-I/II was enhanced in LNCaP cells cultivated in
steroid-free medium. When LNCaP cells were stimulated with
dihydrotestosterone (DHT), estradiol (E2), dexamethasone (DEX),
or anti-androgen drugs, protein expression of the AT1 receptor
and Ang-I/II was augmented. CONCLUSIONS: The present data
suggest that prostatic RAS is overexpressed in HRPC tissue, and
expression of its components is influenced by several kinds of
hormonal stimulation."

Molteni A, Heffelfinger S, Moulder JE, Uhal B, Castellani WJ.
Potential deployment of angiotensin I converting enzyme inhibitors and
of angiotensin II type 1 and type 2 receptor blockers in cancer
chemotherapy.
Anticancer Agents Med Chem. 2006 Sep;6(5):451-60. Review.
PMID: 17017854 [PubMed - indexed for MEDLINE]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17017854>

"There is significant evidence that both angiotensin I
converting enzyme inhibitors (ACEI) and type 1 and type 2
angiotensin 2 (A2) receptor blockers may inhibit tumor growth.
The finding is supported by many reports where these two
classes of drugs showed cytostatic effects on the cultures of
several lines of both normal and neoplastic cells. These drugs
often transformed the cellular biochemical structures,
especially in neoplastic cell lines. The same drugs also
delayed the growth of different types of tumors in a variety of
experimental animals (breast and lung carcinoma in mice;
sarcomas, squamous cell carcinomas and hepatocellular
carcinomas in rats), and there are a few reports of successful
treatment of a limited number of cases of Kaposi sarcoma and
gliomas with these drugs. Retrospective studies in hypertensive
subjects treated with ACEI or A2 receptor blockers also seem to
indicate that the incidence and growth of different neoplasms
was delayed when these patients were compared to hypertensive
patients receiving alternate medications. There is strong
indication that the pharmacologic effect of these drugs may be
exerted by reduction or inhibition of the synthesis of
angiotensin 2. A2 is a powerful mitogen and its effect on
cellular growth is exerted through stimulation of many factors,
including transforming growth factor beta (TGFbeta), epidermal
growth factor (EGF), smooth muscle actin (SMA), and tyrosine
kinase. A2 also regulates apoptotic mechanisms and
angiogenesis. The pharmacologic action of most of these drugs,
however, is not necessarily limited to downregulaton of A2.
Many ACEI, especially those containing the sulfhydryl (SH
group), possess antioxidant or metalloprotease inhibitory
properties per se. These experimental and retrospective data
justify clinical testing of these drugs in appropriate
randomized trials. Several such trials are currently in
process. If these trials confirm the experimental and
retrospective studies, these agents will provide a significant
contribution to the therapeutic treatment of many malignancies
in humans."

Yasumatsu R, Nakashima T, Masuda M, Ito A, Kuratomi Y, Nakagawa T,
Komune S.
Effects of the angiotensin-I converting enzyme inhibitor perindopril
on tumor growth and angiogenesis in head and neck squamous cell
carcinoma cells.
J Cancer Res Clin Oncol. 2004 Oct;130(10):567-73. Epub 2004 Jul 27.
PMID: 15449186 [PubMed - indexed for MEDLINE]
DOI: 10.1007/s00432-004-0582-7
< * w w w .springerlink . com /content/yq19n4pawnfrx2lg/>

"PURPOSE: Recently, it has been reported that angiotensin-I
converting enzyme (ACE) inhibitors have anticancer activity. In
particular, the ACE inhibitor, perindopril, significantly
inhibits tumor growth and angiogenesis in hepatocellular
carcinoma cells along with suppression of the VEGF level.
However, the mechanisms of suppression of the VEGF level are
still unclear, and there are no previous reports on this
subject related to head and neck squamous cell carcinoma
(HNSCC). In some previous studies, angiotensin II, which is
produced from angiotensin I by ACE, directly stimulates VEGF
expression. METHODS: In the present study, we focused upon
angiotensin II, and investigated the effect of perindopril on
VEGF expression, angiogenesis, and tumor development of HNSCC
with in vitro and in vivo studies. RESULTS: In the in vitro
cell proliferation assays, there was no significant difference
between the perindopril-treated group and the control group.
However, the perindoprilat-treated group showed a significant
reduction in mRNA expression of VEGF and inhibited the
induction activity of the VEGF promoter in comparison to the
control group. Perindoprilat treatment also significantly
suppressed angiotensin II production in vitro. In the in vivo
studies, perindopril had a significant inhibitory effect on
tumor growth, and reduced blood vessel formation surrounding
the tumors. CONCLUSIONS: Our findings suggest that perindopril
has no direct cytotoxicity against tumor cells, but has a
potential to inhibit tumor growth due to suppression of VEGF-
induced angiogenesis in vivo. Angiotensin II might have an
important role in carcinogenesis, and the antiangiogenic
activity of perindopril is at least partly mediated by
angiotensin II inhibition. The ACE inhibitor perindopril has
clinical potential as a useful antitumor agent"

Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R,
Nakatani T, Tsujinoue H, Fukui H.
The angiotensin-I-converting enzyme inhibitor perindopril suppresses
tumor growth and angiogenesis: possible role of the vascular
endothelial growth factor.
Clin Cancer Res. 2001 Apr;7(4):1073-8.
PMID: 11309359 [PubMed - indexed for MEDLINE]
< * clincancerres.aacrjournals.org/cgi/content/full/7/4/1073>

Molteni A, Ward WF, Ts'ao CH, Taylor J, Small W Jr, Brizio-Molteni L,
Veno PA.
Cytostatic properties of some angiotensin I converting enzyme
inhibitors and of angiotensin II type I receptor antagonists.
Curr Pharm Des. 2003;9(9):751-61. Review.
PMID: 12570792 [PubMed - indexed for MEDLINE]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=12570792>

"Angiotensin converting enzyme (ACE) inhibitors and angiotensin
II (AII) type 1 receptor antagonists h

"ron" <oitbso@yahoo . com > wrote in message
news:1177015349.762716.184390@e65g2000hsc.googlegroups . com ...
> Again Matti...What is significant here? Mice are so far away from
> humans in terms of disease treatment, and petri dishes and mutated
> cell lines are light years even farther away.

Mice are in fact the animal model for studying prostate cancer. Just
because we are not mice does not mean that research done on them is not very
important.

On Apr 19, 3:27 pm, "George Conklin" <georgeconkl...@earthlink . net >
wrote:
> Mice are in fact the animal model for studying prostate cancer. Just
> because we are not mice does not mean that research done on them is not very
> important.

George...Your two points are indeed correct, but do not address my
earlier point. To restate my point consider:
1) The mouse model for PCa diverges from human PCa experience in a
number of areas
2) PCa has been cured in mice countless times, it still remains a
problem for humans

Now, while the mouse model might be widely used (mainly due to cost
and time factors), it is not very accurate in terms of human
response. In vitro studies are even more removed and consequently of
even less value. This lead to my questioning the import of the study
- which was my point...ron

On 19 Apr 2007 17:24:32 -0700, ron <oitbso@yahoo . com > wrote:

>On Apr 19, 3:27 pm, "George Conklin" <georgeconkl...@earthlink . net >
>wrote:
>> Mice are in fact the animal model for studying prostate cancer. Just
>> because we are not mice does not mean that research done on them is not very
>> important.
>
>George...Your two points are indeed correct, but do not address my
>earlier point. To restate my point consider:
>1) The mouse model for PCa diverges from human PCa experience in a
>number of areas
>2) PCa has been cured in mice countless times, it still remains a
>problem for humans
>
>Now, while the mouse model might be widely used (mainly due to cost
>and time factors), it is not very accurate in terms of human
>response. In vitro studies are even more removed and consequently of
>even less value. This lead to my questioning the import of the study
>- which was my point...ron
>
I think I explained the value of this study for me clearly enough.
Would you care to comment on it? The value of the study was increased
by your comment, which subsequently prompted me to search for other
studies about the potential effects of angiotensin II receptor
blockers and ACE inhibitors on prostate cancer and cancer in general.
This was an unknown area for me until recently, but now without doubt
I'm going to follow it fairly close in future. What makes it even more
interesting topic is that there also natural ACE inhibitors, for
example pomegranate juice, which not surprisingly has both
antihypertensive and anticancer effects.

BTW, what are you saving the sci.med.prostate.cancer for? For the
future generations? ;-). It's been almost dead for ages, I think it's
about time to get some on-topic discussion here. Thank you for
contributing to that. :-)


--
Matti Narkia

On Fri, 20 Apr 2007 03:57:41 +0300, Matti Narkia <mna@mbnet.fi> wrote:

>On 19 Apr 2007 17:24:32 -0700, ron <oitbso@yahoo . com > wrote:
>
>>On Apr 19, 3:27 pm, "George Conklin" <georgeconkl...@earthlink . net >
>>wrote:
>>> Mice are in fact the animal model for studying prostate cancer. Just
>>> because we are not mice does not mean that research done on them is not very
>>> important.
>>
>>George...Your two points are indeed correct, but do not address my
>>earlier point. To restate my point consider:
>>1) The mouse model for PCa diverges from human PCa experience in a
>>number of areas
>>2) PCa has been cured in mice countless times, it still remains a
>>problem for humans
>>
>>Now, while the mouse model might be widely used (mainly due to cost
>>and time factors), it is not very accurate in terms of human
>>response. In vitro studies are even more removed and consequently of
>>even less value. This lead to my questioning the import of the study
>>- which was my point...ron
>>
>I think I explained the value of this study for me clearly enough.
>Would you care to comment on it? The value of the study was increased
>by your comment, which subsequently prompted me to search for other
>studies about the potential effects of angiotensin II receptor
>blockers and ACE inhibitors on prostate cancer and cancer in general.
>This was an unknown area for me until recently, but now without doubt
>I'm going to follow it fairly close in future. What makes it even more
>interesting topic is that there also natural ACE inhibitors, for
>example pomegranate juice, which not surprisingly has both
>antihypertensive and anticancer effects.
>
Here some evidence about pomegranate juice's ACE inhibiting effect:

Aviram M, Dornfeld L.
Pomegranate juice consumption inhibits serum angiotensin converting
enzyme activity and reduces systolic blood pressure.
Atherosclerosis. 2001 Sep;158(1):195-8.
PMID: 11500191 [PubMed - indexed for MEDLINE]
< * w w w .ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11500191>

"Consumption of pomegranate juice which is rich in tannins,
possess anti-atherosclerotic properties which could be related
to its potent anti-oxidative characteristics. As some
antioxidants were recently shown to reduce blood pressure, we
studied the effect of pomegranate juice consumption (50 ml,
1.5mmol of total polyphenols per day, for 2 weeks) by
hypertensive patients on their blood pressure and on serum
angiotensin converting enzyme (ACE) activity. A 36% decrement
in serum ACE activity and a 5% reduction in systolic blood
pressure were noted. Similar dose-dependent inhibitory effect
(31%) of pomegranate juice on serum ACE activity was observed
also in vitro. As reduction in serum ACE activity, even with no
decrement in blood pressure, was previously shown to attenuate
atherosclerosis, pomegranate juice can offer a wide protection
against cardiovascular diseases which could be related to its
inhibitory effect on oxidative stress and on serum ACE
activity."



--
Matti Narkia