How Dexamethasone Works (for the curious)

Greetings All, I got the following off a listserv. I have always wondered how
cancer drugs work so found this to be quite interesting. It sounds good but I
have no idea how true it is.
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Date: Sat, 8 Apr 2006 15:39:54
Reply-To: Alex Maas
Sender: Multiple Myeloma Support List
From: Alex Maas
Subject: How dexamethasone works

For a long time the mechanisms behind the use of glucocorticosteroids
(dex being one of the strongest of these) against MM were something of a
mystery to the medical world. It was simply understood that such drugs
acted as immunosuppressants, as indeed are the same such drugs that are
produced by the body itself in smaller amounts. Since MM consists of a
sort of runaway immune system response involving overproduction of a
specific B cell clone, dexamethasone is a natural approach to slowing
down MM, at the expense of lowering immune system activity against all
sorts of other infections as well.

It was also understood that constant prolonged exposure to
glucocorticosteroid drugs would deregulate the body's carefully tuned
production of steroids and cause all sorts of nasty mischief (hence the
need for slowly tapering off the drug when it is administered steadily
over prolonged periods - it allows the body time to slowly readjust).
The body manufactures glucocorticosteroids as part of its own immune
system regulation system, as well as for control of other related
processes like bone recycling. To get the maximum exposure possible to a
glucocorticosteroid like dexamethasone a short term extremely high dose
is administered. Such a high dose would be absolutely intolerable
(probably lethal) if given steadily over any prolonged time period but
is just barely OK when administered for a very brief period of time. In
such "pulses" there is no need for a taper and, in fact, a taper
actually prolongs the drug exposure period which may not be the best
thing, depending on the frequency of pulses.

So much for the communities "legacy" understanding of dexamethasone. In
the last few years more details of the anti-MM mechanism are understood.
Specifically, it is now understood that dexamethasone (along with other
glucocorticosteroids) somewhat boosts the body's production of a
chemical messenger (IkappaB-alpha protein) that acts to block NF-kappaB.
NF-kappaB is a protein that stands at the gateway of an important B cell
survival pathway. Hence, when NF-kappaB action is blocked, B cells die
off faster and when it is not blocked they survive much longer. Adding
dexamethasone therefore tends to cause immune B cells (such as MM cells)
to die much faster. This, of course, is only true to the extent that the
MM cells are sensitive to suppression of this survival pathway by
dexamethasone.

What unfortunately eventually happens (sooner or later) is that MM B
cells start to produce chemicals (or their bone marrow environment
produces chemicals) that jam the NF-kappaB gateway into a permanently
activated state. Then the MM cells stop dying when exposed to high dose
dexamethasone. One method of overcoming this is to use drugs that are
far more efficient at deactivating NF-kappaB than dex is. Velcade (once
called PS-341) is the latest example of just such a powerful drug.
Another approach is to block the chemicals that jam the NF-kappaB path
"on". Such chemicals include specifically anti-apoptosis proteins such
as the notorious Bcl-2, as well as other things (depending on the strain
of MM). High Bcl-2 levels will render dexamethasone much less effective.
Blocking Bcl-2 activity dramatically restores dexamethasone's MM cell
killing properties. See for example the following URL:


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12521996&dopt=Abstract

One last note about dexamethasone. In cases where dex fails to work one
should note that it also has some bad aspects. Specifically, dex will
boost the production of OPGL and thereby encourage bone recycling
(resorption). Boosting OPGL also actually potentially fuels MM cell
growth. So the whole thing with dex is a double-edged sword where either
the benefit outweighs the negative aspects or vice versa. Just how it
acts depends on the MM and the patient, though I can reassure the list
that it is by far most likely to act to suppress MM than to boost its
growth. Also note that by another mechanism dexamethasone can also kill
nutrient supplies to the bone matrix and thereby actually kill bone
(avascular necrosis) leading to hip problems, etc. Some on this list
know all about this sort of thing. It maybe that muscle weakness also is
caused by the cell nutrient deprivation aspects of dex.

This is perhaps too technical but I hope not - and I hope it helps
provide a reasonably clear answer to Paul's excellent question. Only a
few years ago his question would have been much harder to clearly answer
but medical understanding has a long way in a short time and continues
at a remarkably accelerated pace.

Best wishes,

Bob Meyer in San Diego county NO formal medical training but former
caregiver to wife (Patricia) dx'd rare extremely aggressive IgG kappa MM
with plasmablastomas and M-spike of 1100 in 4/98, died 11/98 at age 52;
prev. MS history; also hepatitis, severe mono

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