Interesting new article
Ed Friedman
androgen ablation (IAA) with testosterone (T) and finasteride (F) in the
off-cycle, produces tumor of ~5 times less size than what results from
continuous androgen ablation (CAA) or standard IAA. The abstract can be
seen at:
http://www3.interscience.wiley.com/cgi-bin/abstract/112221624/ABSTRACT
What is interesting is that within the full article, they mention that
the apoptotic proteins (produced by mAR, according to my model) are seen
shortly after T plus F is added following androgen ablation, but not
seen in the absence of androgen ablation. This is consistent with iAR
downregulating the apoptotic proteins upregulated by mAR. It is known
that stimulation of mAR causes responses in a much quicker time frame
than stimulation of iAR does.
In practice, what this means is that anyone doing IAA should do much
better with very high dose T with F at the point that the androgen
ablation is ended. It also raises the tantalizing possibility that very
high dose T plus Casodex may just blow away almost all prostate cancer
cells.
Ed Friedman
Bill
(finasteride) - right?
In the full text do they cite to their "previous studies [that] suggest
that relative to dihydrotestosterone (DHT), testosterone (T) is a weak
inducer of proliferation and a more potent inducer of differentiation?"
Last time I saw my uro I asked him what he thought about putting me on
Proscar and he snidely rejected the notion, saying that T was the
problem, not DHT. Obviously he is a little behind in his reading.
Bill Denton
RP 2/12/02
PSA .67
Memphis
Ed Friedman
Bill,
You ask some excellent questions. Taking your last question first, the
papers they cite are:
1) "Androgen-induced regrowth in the castrated rat ventral prostate:
Role of 5alpha-reductase", Wright AS et al., Endocrinology 1999;140(10):
4509-4515
2) "Relative potency of testosterone and dihydrotestosterone in
preventing atrophy and apoptosis in the prostate of castrated rat",
Wright AS et al., J Clin Invest 1996;98(11): 2558-2563
3) "Finasteride dose-dependently reduces the proliferation rate the
LNCaP human prostatic cancer cell line in vitro", Bologna M et al.,
Urology 1995;45(2): 282-290
As to your first question, no, I did not make a mistake when I suggested
that high T plus Casodex might be an effective treatment. There is no
question that high T plus Proscar will not blow away prostate cancer
(PCa). The best that Dr. Leibowitz has observed is a slow steady
decline in PSA for PCa patients (including those who have had RP,
meaning that the decline in PSA is really indicating a decline in PCa).
In February, 2005, researches from Athens, Greece published a paper
proving that membrane androgen receptor (mAR) exists and proving that
this receptor produces apoptotic proteins that destroys PCa. In my
opinion this is the biggest discovery in PCa in over 50 years. Now,
before this article, there would be no reason to even consider a
combination such as T plus Casodex, since they would seem to cancel out
each other. Now, knowing that there are two different androgen
receptors (and knowing that Casodex blocks iAR but not mAR), and not
just one, it is totally logical to try to block the one causing the
trouble, and stimulate the one that will kill off the PCa. Basically, T
plus Casodex (or even T plus Proscar plus Casodex, since there is
evidence that T binds to mAR more strongly than DHT does) should
maintain a high level of apoptotic proteins and maximize the rate for
killing PCa. The only way that T plus Casodex would make PCa grow
faster than with Casodex alone, is if there is a mutation that prevents
mAR from producing apoptotic proteins, which should be an extremely rare
mutation, because the total absence of mAR produces apoptosis via a
different mechanism (essentially the same way that ADT does).
This is all very complicated, and hopefully my next paper will explain
things a little clearer. Ideally, researchers will follow through with
studies to prove just how effective T plus Casodex are. Until the
research is done, the only thing that I can do is to speculate based on
what my model predicts.
Finally, the fact that your uro is not up on the latest research does
not mean that he is a bad uro. The way medicine works is that it takes
years from the time breakthrough research occurs before the animal
studies are done, and then the human studies are done, and then a few
years after that point you should expect it to become common knowledge
among the doctors who are actually treating patients. However, any
doctor who thinks he is current with the latest research regarding PCa
and who is ignorant about mAR, is not really that current.
Ed Friedman
Bill
comment and was speculating how this study indirectly supported your
model.
I saw those titles in my search but did not read them because they were
so ancient. I was expecting something recent that would explain why my
uro wasn't up on the fact that, as they state, T appears less
responsible for PCa proliferation than DHT. Is it not now accepted that
that is the case? I want a doctor who reads everything there is on PCa
and incorporates it all into his own understanding of the disease and
how to treat it.
Ed Friedman
Bill,
I don't think that most doctors are up the literature, no matter what
their specialty is. Usually, researchers stay on top of the literature,
try to make the advances, and if successful in making a breakthrough,
try to get the doctors who treat the patients to start to take advantage
of that breakthrough. I would expect that the typical uro learns most
of what they know from med school and residency, then keep up by
attending conferences with other doctors. Not many doctors have the
time or ability to scan the literature and read all of the articles that
come out in their specialty. That is one of the reasons that I am so
impressed with Dr. Leibowitz. When I spoke with him, he demonstrated an
almost encyclopedic knowledge about prostate cancer research. He had
read all of the key articles and knew many of the researchers on a
personal level. Also, he didn't just read articles - he analyzed them
thoroughly if that is what it took to fully understand them. E.g., when
he read the Fowler and Whitmore paper (which all doctors learn in med
school shows that T is bad), he took the time to read every reference
cited, and to independently analyze the raw data himself before coming
to the conclusion that the Fowler and Whitmore paper was fatally flawed.
The first uro that I went to (who had an extremely good reputation) had
almost no knowledge about T and prostate cancer (PCa). He knew that the
Fowler and Whitmore paper had demonized T, but he didn't even know what
decade that paper came out in or any of the details within that paper. I
have no idea what accepted beliefs are among uros, but I suspect that
most are like the one I encountered.
If your goal is to get a Proscar prescription, then by all means try to
find a uro who will prescribe it. However, you should be aware that in
the full article that I cited, they showed that adding finasteride (F)
alone had very little effect. Only the T plus F group showed
significant improvement over all of the other treatment groups. What
this means in practice is that the positive effects of the F you take
depends on the level of T you have. At the lowest levels of T, F should
have little or no effect. As the level of T increases, the positive
effects with F should also increase. Even if you understand this and
believe it to be true, most uros will refuse to administer T to PCa
patients under any circumstances. I'm only aware of three doctors in
this country (2 in L.A. and 1 in Chicago) who would administer T with F
(but there could always be others that I am not aware of).
Ed Friedman
Bill
spammed about + F would be of benefit? :-)
Ed Friedman
Bill,
I would suggest that you save your money. Even for those spams which
offer products that actually raise your level of T, the end result is no
gain. This is because your body reacts to detecting a higher level of T
by shutting down T production and/or increasing SHBG production to bind
up the T. The only way to effectively raise your T is with a doctor who
knows what he is doing.
Ed Friedman