[MOL] Re: [ANGIOGEN] George Matthews' question [02419] Medicine On Line

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[MOL] Re: [ANGIOGEN] George Matthews' question

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>X-Mailer: Microsoft Internet Mail 4.70.1155
>Date:         Wed, 28 Oct 1998 18:36:55 +0200
>Reply-To: "ANGIOGEN: Current Research on Angiogenesis"
>Sender: "ANGIOGEN: Current Research on Angiogenesis"
>From: Miri <miri1307@NETVISION.NET.IL>
>Subject:      Re: [ANGIOGEN] George Matthews' question
>Dear Charles,
>I was very happy to read your e-mail, and I have a few questions for you:
>1. Are trials already being made with anti-angiogenesis compounds on
>humans? 2) what about treatment with these compounds for cases of localized
>osteosarcoma in humans?
>The 9-year old son of my boyfriend was diagnosed 2 months ago with this
>devastating disease and so far he has not responded adequately to chemo
>(which he is getting ever since on a weekly basis). Could you please give
>me more info on this compound, etc.? I would be very greatful for your
>answer because I will leave no stone unturned to help this child (or any
>other if I can, for that effect!).
>Thanks very much,
>> From: Harmon, Charles {ONCO~Nutley} <CHARLES.HARMON@ROCHE.COM>
>> Subject: George Matthews' question
>> Date: יום שלישי 27 אוקטובר 1998 23:00
>> This is a reply to George Matthews' question (Oct. 27) "...will [the new
>> anti-angiogenesis compounds] be effective in multiple tumor sites, or
>> will it prove to be only effective in single tumor sites ?".  I am a
>> scientist in the pharmaceutical industry, and I lead a drug discovery
>> project that targets tumor angiogenesis by blocking the activity of
>> certain proteins on the cell membranes of endothelial cells (i.e. the
>> cells that constitute the blood vessel).  In my view the answer to
>> George's question is that we would expect a potent antiangiogenic agent
>> to block tumor angiogenesis, and hence expansion of tumor mass, in
>> multiple sites in the body - there is no scientific rationale for
>> restriction of activity to a single tumor site.  Although most cancer
>> research with antiangiogenic (and other) agents involves models in which
>> the growth of a single experimental tumor in each animal is studied,
>> there have also been studies of the growth of multiple experimental
>> metastases that address the question directly.  Judah Folkman's group at
>> Harvard have shown that angiostatin, a selective inhibitor of
>> endothelial cell growth discovered by Michael O'Reilly working with
>> Folkman, completely blocks the growth of established micrometastases in
>> the mouse lung ("Lewis Lung" model).  In this model a large number of
>> microscopic lung metastases are formed by dissemination of tumor cells
>> from the primary tumor, which is placed under the skin of the mouse at
>> the start of the experiment.  These lung micrometastases remain
>> "dormant" (i.e. microscopic in size) because their growth is suppressed
>> by angiostatin produced by the primary tumor (which does not suppress
>> its own growth, for reasons I won't go into here). Folkman believes that
>> this phenomenon also occurs in some human cancers.  When the primary
>> tumor (under the skin of the mouse) is cut away surgically, the many
>> lung micrometastases quickly begin to grow and the mouse soon dies from
>> the tumor burden. The metastases take off because they are no long
>> exposed to circulating angiostatin and so are capable of inducing blood
>> vessel growth.  However, if purified angiostatin is given to the mice by
>> injection, starting right after surgical removal of the primary tumor
>> under the skin, these many micrometastases do NOT grow and the mouse
>> survives indefinitely (i.e. as long as treatment continues).
>> George Matthews writes: "It would seem that treating multiple tumor
>> sites by shutting down the blood supply to them would also kill the
>> patient especially if there are numerous mets".  Again, I do not see a
>> rationale for this concern.  Certainly antiangiogenic agents are
>> expected to have side effects associated with inhibition of
>> physiological angiogenesis, such as that occuring in wound healing and
>> in the uterus during menstruation.  Also, the drug would likely be
>> teratogenic (i.e. cause birth defects), assuming that vasculogenesis, or
>> blood vessel development, is also inhibited. However, we believe that
>> these side effects will be relatively easy to manage clinically,
>> especially in comparison with those suffered by patients undergoing
>> conventional chemotherapy.  Indeed, the expectation of a high
>> "therapeutic index" is one of the chief advantages of an antiangiogenic
>> approach to anticancer drug discovery.  We expect to be able to treat
>> patients indefinitely with antiangiogenic agents, including in the
>> adjuvant setting, (i.e. after removal of primary tumor by surgery or
>> radiation, when the presence of micrometastases is thought likely but
>> none can be detected). Even if the metastases are not eradicated, the
>> idea is to keep them growth-suppressed by continuous antiangiogenic
>> therapy so that the patient can continue a relatively normal life,
>> ultimately "to die with cancer, but not of cancer".  The hope is that
>> cancer will become a disease than can be successfully managed, in much
>> the same way as we now manage hypertension.
>> Charles Harmon.
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