And to your other point, the only way to know how Tpo will impact clinical
practice is to conduct clinical trials.  Just because Tpo is produced in
many organs doesn’t really tell you that much.  Leukine (GM-CSF) is produced
by endothelial cells of the vasculature, which are everywhere. Did that
prevent Leukine from being used clinically?  Nope. (Of course, GM-CSF is
produced by other cells, too.) What may be most important is how growth
factors interact in the bone marrow microenvironment, a model which
still defies easy analysis. Pharmacologic doses of a cytokine may make up
for deficiencies in the local milieu of the marrow. This seems to be the
case for Tpo, where preclinical murine experiments were very impressive.
In fact, so much, that I myself worry about lineage steal, something we’ve
not yet seen with the existing clinical cytokines.

Finally, not having read the NY Times article, is Genentech involved?
I thought it was Zymogenetics!  E-mail me back if it’s really Genentech.
–Gary

–
Gary Takahashi            |  
Hematology Clinic         |  
9155 SW Barnes Road #530  |  
Portland, OR  97225       |  

>>> On 22 Jun 1994 06:32:21 GMT, takah…@ohsu.edu (Gary W. Takahashi) said:
> We don’t yet know if patients receiving chemotherapy are relatively
> deficient in thrombopoietin (Tpo).  This is one of the things that
> will have to be measured.  Recall that we didn’t know that patients
> getting chemotherapy were deficient (sometimes) in erythropoietin
> (Epo), and now, Ortho-Biotech has FDA approval for use of Epo in
> cancer/chemotherapy related anemia.

It seems to me that it was quite reasonable to suspect that patients
getting chemo were sometimes deficient in Epo.  Many chemotherapy
agents are toxic to the kidneys (where Epo is produced).  Most
patients getting chemotherapy are getting tons of fluids IV and the
kidneys are working overtime to try and flush these fluids out.  It
seems reasonable (to me) that under such stress they are less able to
produce Epo.  Apparently Tpo is produced in many places in the body
and seems to me less likely than Epo to be deficient.

According to the NY Times article, Tpo was discovered using pigs.  The
pigs were irradiated, presumably to kill (some of?) the bone marrow.
This would subsequently produce a shortage of platelets and increase
the amount of Tpo produced.  This was then filtered from the pig’s
blood (in a process that I do not completely understand).  This is not
exactly like patients undergoing chemo, but is pretty similar.  So it
seems that most patients on chemo would have more than enough Tpo.

>  A second point to be raised:
> oncologic advances in the area of high-dose chemotherapy or
> dose-intensification have been hampered by the fact that we had no
> way of boosting platelet counts as we can with neutrophils.
> Platelet transfusions work up to a point, but patients can become
> refractory and there is risk of transfusion-borne infection.

I understand this.  As I pointed out in my original article it may be
of use to post bone marrow transplant patients some of whom have a
somewhat chronic need of platelets.

My principal questions about Tpo were what was the market (that is
should someone buy Genetech stock, based on this announcement ?
According to the newspapers this is a $1 billion/ year drug.  Even at
$200/dose (my guess at the price based on the price of Epo, G-CSF and
GM-CSF) this is 5,000,000 doses.  I do not see that many people
needing Tpo.

My second (much more important) question is, is this going to be a
‘miracle’ drug for cancer patients.  I think it will be useful for a
few patients, but most will not need it.

Art

fla…@cli.com
Computational Logic, Inc.
Austin, Texas

As I understand it, Tpo is a megakaryocyte maturation factor, and not
a megakaryocyte colony-stimulating factor, as is GM-CSF and IL-3.  Perhaps
using the two cytokines in combination will help to boost the number of
stem cells with Tpo-receptors, such that the relative lack of megakaryocytes
can be overcome.
–Gary

–
Gary Takahashi            |  
Hematology Clinic         |  
9155 SW Barnes Road #530  |  
Portland, OR  97225       |  

>First a technical one, does anyone know where in the body
>thrombopoetin is produced?

Liver, spleen, muscles, and kidneys.  They don’t know why.  This is from a
long article on thrombopoetin in today’s New York Times.

Ken Shirriff                    shirr…@cs.Berkeley.EDU

> >>> On Tue, 21 Jun 1994 21:29:59 GMT, cr…@microunity.com (Craig Hansen) sai

> > Myelodysplastic Syndromes (MDS, aka Myelodysplasia, aka
> > pre-leukemia) are conditions in which the stem cells do not
> > properly differentiate into platelets (and/or red cells, white
> > cells). Thrombopoetin holds much promise of saving the lives of

                                ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
> > about 10,000 patients from MDS, which under today’s
> > state-of-the-art has a prognosis of about 2-5 year lifespan for the
> > most mild forms. MDS is also a secondary condition of chemotheraphy
> > and other cancers.

   While there is no conclusive evidence that growth factors (particularly
myeloid growth factors like G-CSF) accelerate the leukemic transformation of
MDS, there is no evidence that the differentiating effect retards this
tendency to transform to leukemia. I believe the same will hold true with
thrombopoetin. It is premature to be too optimistic at this stage to say that
the drug holds promise of "saving lives" in patients with MDS.

—————————————————————————-
Dr. Alan Teh                                           fax:    603 7562253
Kuala Lumpur               M A L A Y S I A           phone:    603 7502867
—————————————————————————-

I do not know a whole lot about MDS.  I did read the statement in
cancernet about it.  According to that statement most patients
actually have too much Erythropoetin (Epo).  Seems likely they also
have too much thrombopoetin as well.  On the other hand some patients
have too little Epo and may benefit from the use of Epo.  So some may
also benefit from Tpo as well.  I wonder how much of an increase in
average lifespan this represents, though.

Art

fla…@cli.com
Computational Logic, Inc.
Austin, Texas