Re: study of interest: AMD3100 and Rituximab

[Guest guest]

At 09:16 AM 6/23/08, KarlS wrote:

>Study of AMD3100 and Rituximab in Patients With Chronic Lymphocytic

>Leukemia or Small Lymphocytic

>Lymphoma

><http://clinicaltrials.gov/ct2/show/NCT00694590>http://clinicaltrials.gov/ct2/s\

how/NCT00694590

>SNIP......... The purpose of this research study is to determine if

>AMD3100 can release CLL/SLL cells into the blood and make them more

>sensitive to killing by rituximab......

In addition to releasing CLL cells for rituximab to kill, AMD3100 has

the potential to prevent any residual CLL cells from spreading and

being nurtured within stromal tissues, where new proliferation of

rituximab-resistant CLL cells might occur.

AMD3100 is a small peptide that inhibits signaling of the CXC

chemokine receptor-4 (CXCR4), which binds its ligand, which is

stromal cell-derived factor-1 (SDF-1 or CXCL12). When CXCR4 is

expressed on cancer cells and binds SDF-1, the cancer cells

matastasize, i.e. are directed to stromal tissues, e.g. lymph

nodes. CXCR4 binding of SDF-1 can also result in biochemical events

leading to nurturing angiogenesis within stromal tissues.

As such, besides causing the original population of CLL cells to be

released into blood, AMD3100 would also be expected to inhibit

migration of residual rituximab-resistant CLL cells to nurturing

stromal tissues, where they would be more protected from undergoing apoptosis.

Background information about AMD3100 is included the journal

reference for recent press releases related to its use for colon

cancer. Links are below.

Al Janski

New Weapon For Attacking Tumor Invasion And Metastasis (ScienceDaily

(June 21, 2008)

http://www.sciencedaily.com/releases/2008/06/080617093700.htm

Journal reference:

Li et al. Inhibition of CXCR4 activity with AMD3100 decreases

invasion of human colorectal cancer cells in vitro. World Journal of

Gastroenterology, 2008; 14 (15): 2308 DOI:

<http://dx.doi.org/10.3748/wjg.14.2308>10.3748/wjg.14.2308

http://www.wjgnet.com/1007-9327/14/2308.asp

[Guest guest]

" In vitro, AMD3100 has shown a significantly inhibitory effect on invasion and

migration in colorectal cancer cell line. This effect can be further enhanced at

higher concentration. "

Thanks for sharing that, Al... I think there are two caveats to consider,

however. The first being that in vitro models are not very good at predicting

effects in the body of humans, and the second is that effects of biologics and

drugs may be very different for CLL than for colorectal cancer cells.

Best

~ Karl

Re: study of interest: AMD3100 and Rituximab

At 09:16 AM 6/23/08, KarlS wrote:

>Study of AMD3100 and Rituximab in Patients With Chronic Lymphocytic

>Leukemia or Small Lymphocytic

>Lymphoma

><http://clinicaltrials.gov/ct2/show/NCT00694590>http://clinicaltrials.gov/ct2/s\

how/NCT00694590

>SNIP......... The purpose of this research study is to determine if

>AMD3100 can release CLL/SLL cells into the blood and make them more

>sensitive to killing by rituximab......

In addition to releasing CLL cells for rituximab to kill, AMD3100 has

the potential to prevent any residual CLL cells from spreading and

being nurtured within stromal tissues, where new proliferation of

rituximab-resistant CLL cells might occur.

AMD3100 is a small peptide that inhibits signaling of the CXC

chemokine receptor-4 (CXCR4), which binds its ligand, which is

stromal cell-derived factor-1 (SDF-1 or CXCL12). When CXCR4 is

expressed on cancer cells and binds SDF-1, the cancer cells

matastasize, i.e. are directed to stromal tissues, e.g. lymph

nodes. CXCR4 binding of SDF-1 can also result in biochemical events

leading to nurturing angiogenesis within stromal tissues.

As such, besides causing the original population of CLL cells to be

released into blood, AMD3100 would also be expected to inhibit

migration of residual rituximab-resistant CLL cells to nurturing

stromal tissues, where they would be more protected from undergoing apoptosis.

Background information about AMD3100 is included the journal

reference for recent press releases related to its use for colon

cancer. Links are below.

Al Janski

New Weapon For Attacking Tumor Invasion And Metastasis (ScienceDaily

(June 21, 2008)

http://www.sciencedaily.com/releases/2008/06/080617093700.htm

Journal reference:

Li et al. Inhibition of CXCR4 activity with AMD3100 decreases

invasion of human colorectal cancer cells in vitro. World Journal of

Gastroenterology, 2008; 14 (15): 2308 DOI:

<http://dx.doi.org/10.3748/wjg.14.2308>10.3748/wjg.14.2308

http://www.wjgnet.com/1007-9327/14/2308.asp

[Guest guest]

At 03:42 PM 6/23/08, KarlS@... wrote:

> " In vitro, AMD3100 has shown a significantly inhibitory effect on

>invasion and migration in colorectal cancer cell line. " ...........

>in vitro models are not very good at predicting effects in the body

>of humans, and the second is that effects of biologics and drugs may

>be very different for CLL than for colorectal cancer cells.

Apparently, the purpose of my reference to the recent news release

(about colon cancer & AMD3100) was misunderstood.

That reference was not evidence of what effects AMD3100 might have on

CXCR4 receptor function (or any other effect) in CLL patients. It

was intended only as an example of another cancer being treated by

AMD3100 with the strategy of antagonizing CXCR4 signaling; i.e. it's

an example of CXCR4-dependent AMD3100 function. Even the knowledge

of AMD3100's effects on CXCR4 on cells in general is by no means

limited to the Gastroenterology paper referenced in that press release.

It is well-established that:

1. AMD3100 is a CXCR4 antagonist

and

2. CXCR4 receptor is important in CLL cell pathogenesis, especially

those pathologies related to migration of CLL cells.

Thus, it is reasonable to expect that AMD3100 would inhibit migration

of CLL cells (in vitro or in vivo).

As a matter of fact, I expect the mechanism by which AMD3100 is

expected (by the clinical researchers) to cause CLL cells to move

into the blood during the subject clinical trial is probably through

antagonism of CLL CXCR4 receptors.

Dr. Kipps, for one, has many published results demonstrating the role

of CXCR4 in CLL pathogenesis. One of his first is from 1999, i.e.

" Chronic Lymphocytic Leukemia B Cells Express Functional CXCR4

Chemokine Receptors That Mediate Spontaneous Migration Beneath Bone

Marrow Stromal Cells " Blood, Vol. 94 No. 11 (December 1), 1999: pp.

3658-3667;

FULL-TEXT:

http://bloodjournal.hematologylibrary.org/cgi/content/full/94/11/3658

A few years ago, Dr. Kipps & coworkers published results of other

peptide inhibitors (AMD3100 is a peptide) of CXCR4 in CLL, i.e.

" Small peptide inhibitors of the CXCR4 chemokine receptor (CD184)

antagonize the activation, migration, and antiapoptotic responses of

CXCL12 in chronic lymphocytic leukemia B cells " Blood, 1 September

2005, Vol. 106, No. 5, pp. 1824-1830;

FULL-TEXT:

http://bloodjournal.hematologylibrary.org/cgi/content/full/106/5/1824

Off-hand, I do not recall whether or not any of the CLL/CXCR4

publications have in vivo human evidence that CXCR4 signaling is

inhibited by CXCR4 antagonists. However, in vivo human evidence is

lacking for biochemical mechanisms of many CLL drugs.

Although the mechanism by which a given drug is efficacious is not

always the mechanism that was theorized prior to initiation of

clinical trials, having some idea about biochemical mechanism is an

important prerequisite for design of those clinical studies........,

a direction at which to 'start' to sail..........

Hopefully, this helps.

Al Janski

[Guest guest]

Many people have been working on this idea for a long time.  The problem with

CLL cells finding 'sanctuary' in lymph tissue has been identified as a problem

for many years.

In fact, I wrote and called the company urging trials for CLL.  I was assured

that trials for CLL would be forthcoming.  I guess at least one trial is here. 

(I don't claim credit for this, I'm sure the trial was already being planned.)

Bulky nodes is a real problem for CLL. 

I do wonder what this drug would do by pushing out stem cells into the blood. 

It might not be a drug one could take for an extended period of time.

From: KarlS@... <KarlS@...>

Subject: study of interest: AMD3100 and Rituximab

nhl-info , ,

PAL-datafork

Date: Monday, June 23, 2008, 7:16 AM

I recall having a conversation with (of CLLtopics) regarding

this very

idea, perhaps five years ago? , you are indeed a creative

thought-leader in the community ... and deserving of thanks for all that you

do.

~ Karl

PS That's not to say this or any great idea will necessarily work in

practice, but it seems a clever one to me and deserving of testing.

==

Study of AMD3100 and Rituximab in Patients With Chronic Lymphocytic Leukemia

or Small Lymphocytic Lymphoma

Information provided by:Genzyme

ClinicalTrials. gov Identifier:NCT00694 590

The purpose of this research study is to determine if AMD3100 can release

CLL/SLL cells into the blood and make them more sensitive to killing by

rituximab, an anti-cancer drug that is commonly used in treating CLL and

SLL. In this study, AMD3100 will be added to standard treatment with

rituximab. Subjects will be monitored to see how well they tolerate the use

of these drugs together and how well they work to treat the leukemia.

The study is divided into Part 1 and Part 2. The purpose of Part 1 of the

study is to find the highest dose of AMD3100 used with rituximab that can be

given safely. The purpose of Part 2 of the study is to find out what effects

(good and bad) that AMD3100, when used with rituximab, has on the subject

and his/her leukemia.

http://clinicaltria ls.gov/ct2/ show/NCT00694590

All the best,

~ Karl