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893ANTIANGIOGENIC THERAPIES(September 1998)

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  • Janice and Ben Haines
    Sep 20, 1998
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      LIST OF PROMISING ANTIANGIOGENIC THERAPIES
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      Last updated: September 20, 1998

      Definition of Angiogenesis:
      ..(anti) blood vessel (angio) origination (genesis). Preventing the growth of
      blood vessels, ideally, would starve the deadly tumors to death.

      Compiled by the NHL-low mailing list. A mailing list setup to track
      conventional therapies that may lead to the cure for low grade lymphoma.

      For past posts and directions on subscribing go to:

      http://www.egroups.com/list/nhl-low

      Current status and other information is unverified,

      Regards,
      -Ben(KIA)
      (I am a rookie researcher, computer consultant, who runs a mailing list
      dedicated to his wife and others fighting low grade lymphoma. We understand
      'INFORMATION IS POWER and we EXPECT TO WIN.")

      Most of the below information taken off NCIs newly updated TERRIFIC web
      site, a section entirely devoted to angiogenesis inhibitors and cancer.

      http://207.121.187.155/NCI_CANCER_TRIALS/zones/PressInfo/Angio/

      (To me this is a huge sign of increased enthusiasm from NCI/the cancer
      world on angiogenesis inhibitors. Also, please note the newest agreement
      --September 1998 -- with NCI in regards to Endostatin. I don't think I have
      to spell out my enthusiasm: beyond cautiously optimistic.)

      NHL-low keeps a seperate list for WORLDWIDE angiogenesis inhibitors for
      tracking purposes (such as: COMBRETASTATIN A-4). Also, actual results will
      eventually be added as they are made available.

      ----8<---------8<------

      ANTIANGIOGENIC THERAPIES
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      CAI
      - Inhibits influx of calcium into cells, suppressing proliferation of
      endothelial cells
      - Phases I and II
      Mechanism: Unknown; Non-specific inhibitor cell invasion and motility
      -----------------------------------------------------------------------------
      CM101
      - Induces inflammation in tumors destroying growing capillaries
      - Phase I
      Mechanism: Unknown
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      INTERFERON ALPHA
      - Decreases production of the angiogenic
      protein FGF (made by tumor cells)
      - Phase III (hemangiomas in infants)
      Mechanism: blocks factors that stimulate the formation of blood vessels;
      Inhibits release of endothelial growth factor
      Commercially Available
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      INTERLEUKIN-12
      - Increases production of an angiogenic
      inhibitor called inducible protein 10
      - Phase I/II
      Mechanism: Natural inhibitor of angiogenesis; Inhibits endothelial cell growth
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      MARIMASTAT
      - Inhibits the enzymes that cells employ when
      migrating through tissue
      For: pancreas, lung, gastric and breast cancers and glioma
      - Matrix metalloproteinase (MMP) inhibitors block enzymes secreted by
      cancer cells, which help blood vessels to spread by breaking down the
      surrounding tissues. The most advanced in clinical trials is Marimastat.
      - Phases III
      - British Biotech, Inc., Annapolis, Md.
      Mechanism: Prevents new blood vessels from invading surrounding tissue;
      Synthetic inhibitor of matrixmetalloproteinases (MMPs)
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      PENTOSAN POLYSULFATE
      - Blocks action of growth factors on endothelial cells
      - Phase I
      Mechanism:
      ----------------------------------------------------------------------------
      PLATELET FACTOR 4
      - Inhibits proliferation of endothelial cells
      - Injected intravenously to treat lymphoma (lymphoma is not listed anymore?
      9/98) now says: Kaposi's Sarcoma, renal melanoma, and colon carcinoma.
      - Phase II
      Mechanism: Natural inhibitor of angiogenesis;Inhibits endothelial
      cell growth
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      THALIDOMIDE
      For: Brain Cancer, Kaposi's Sarcoma, Prostate Cancer, Breast Cancer,
      Macular Degeneration, primary brain cancers
      - Phase II
      - EntreMed, Inc., Rockville, Md.
      Mechanism: Unknown; Synthetic Sedative
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      TNP-470 (a.k.a.: AGM-1470)
      - a fumagillin byproduct
      - Phase I (this changed from phase II 9/98) against pediatric cancers
      (keep your eye on leukemia/lymphoma trials set to commence end of 1998 for
      peds, funny how NCI isn't publicly mentioning this but note the solid
      tumors in the next line. Could someone e-mail me why information is kept
      secret and I have to spend 100s of hours trying to squeeze the smallest
      drop of information out of all the mountains of data? Your industry, stuck
      in the early 1980s, as far as basic information gathering goes, drives me
      nuts.) Phase I against advanced cancer for adults with solid tumors.
      - TAP Pharmaceuticals Inc., (a joint venture between Japan's Takeda
      Pharmaceuticals and Abbott Laboratories)
      - Weaker first generation inhibitor
      Mechanism: Interrupts function of dividing endothelial cells; Selectively
      inhibits proliferation and migration of endothelial cells
      ------------------------------------------------------------------------
      SQUALAMINE
      - an inhibitor of angiogenesis extracted from the dogfish shark, is
      beginning clinical trials in cancer patients. It is the first of a new
      class of natural molecules
      - Phase I
      - Magainin Pharmaceuticals, Inc., PlymouthMeeting, PA
      Mechanism: Unknown; Extract from dogfish
      shark liver; inhibits sodium- hydrogen exchanger, NHE3
      ------------------------------------------------------------------------
      VITAXIN
      -First drug candidate in the clinic that specifically binds to the
      Integrin receptor. This receptor is preferentially expressed on newly
      sprouting blood vessels that supply oxygen and nutrients to rapidly
      growing tumors
      - Phase I
      - Ixsys, Inc. San Diego, Calif.
      Other:
      "VITAXIN is a humanized derivative of the mouse LM609 monoclonal antibody
      that is directed to integrin (alpha)v(beta)3, noted the researchers."
      - considered second generation of inhibitors
      RESULTS:
      "In the phase I clinical trial, 17 patients were treated. All of the
      patients had stage IV disease (2=breast cancer, 4=colon, 2=sarcoma, 2=lung,
      3=kidney, 1=ovarian, 1=cloacogenic, 1=paratoid, and 1=cervical), an ECOG
      performance status of (<=)2, and had failed prior chemotherapy."
      "There was one patient who had a partial response, seven who had stable
      disease, and six who had disease progression. Patients who demonstrated a
      partial response or stable disease at week eight were eligible for
      retreatment, noted the researchers."
      Mechanism: Prevents new blood vessels from invading surrounding tissue;
      Antibody to integrin, present on endothelial cell surface
      ------------------------------------------------------------------------
      RhuMab
      - VEGF
      - Genentech, Inc., South San Francisco, Calif.
      - www.gene.com
      - Phases II and III against lung, breast, prostate, and colorectal cancer
      - Monoclonal antibody to vascular endothelial growth factor (VEGF)
      Mechanism: blocks factors that stimulate the formation of
      blood vessels
      My notes: Keep a close eye on this one, it might be huge for heart disease
      as well. Look in the archives of NHL-low for more information.
      Patient Hotine for these trials: 650-225-5300
      ------------------------------------------------------------------------
      SU5416
      - blocks the enzyme tyrosine kinase
      - Sugen, Inc., Redwood City, Calif.
      - Phase I
      - Molecule that blocks VEGF receptor signaling
      Mechanism:blocks factors that stimulate the formation of
      blood vessels
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      BAY 12-9566
      For: Against lung and prostate cancers
      - Bayer Corp., West Haven, Conn.
      - Phase III against lung and prostate cancers
      Mechanism: prevents new blood vessels from invading surrounding
      tissue;Synthetic inhibitor of matrixmetalloproteinases (MMPs)
      ------------------------------------------------------------------------
      AG3340
      For: Against lung and prostate cancers
      - Agouron Pharmaceuticals, Inc., LaJolla, Calif.
      - Phase III against lung and prostate cancers
      Results:
      "In its latest report, Agouron said disease was stabilized in more than 25%
      of 47 patients in a Phase I study on patients with advanced lung, prostate,
      kidney and colorectal cancers and sarcoma and melanoma."
      Mechanism: prevents new blood vessels from invading surrounding
      tissue;Synthetic inhibitor of matrixmetalloproteinases (MMPs)
      ------------------------------------------------------------------------
      COL-3
      - CollaGenex Pharmaceuticals, Inc., Newton, Pa.
      - Phase I
      Mechanism: prevents new blood vessels from invading surrounding tissue;
      Antibiotic derivative that inhibits MMPs
      ------------------------------------------------------------------------
      CM101
      - Carbomed, Brentwood, Tenn.
      - Phase I
      Mechanism:
      ------------------------------------------------------------------------
      COMBRETASTATIN A-4
      - A synthetic derivative of a natural product extracted from the African
      bush willow, is about to start clinical trials
      - (COA-4) and its soluble prodrug. Both bind to tubulin and
      cause endothelial cell damage
      - Oxigene, Inc.
      Mechanism:
      ------------------------------------------------------------------------
      CARBOXYAMIDOTRIAZOLE
      - Carboxyamidotriazole plus Paclitaxel (for refractory lymphomas Phase I)
      ------------------------------------------------------------------------
      SURAMIN
      -Parke-Davis Morris Plains, N.J.
      -Phases II and III against hormone-refractory prostate cancer
      Mechanism: Unkown; Non-specific multi-site effects
      ------------------------------------------------------------------------
      CT-2584
      - unique mechanism of action of tumor-cell killing. This mechanism involves
      CT-2584's effect on tumor-cell phospholopids such as phosphatidic acid
      (PA)
      For: begin Phase II trials this year in both advanced prostate cancer and
      in advanced sarcomas
      - Cell Therapeutics, Inc.
      Results:
      "Of the 18 patients evaluable for tumor response, 13 remain alive at a
      median of eight months (range 2-19 months) out from treatment with CT-2584.
      Five patients (27%) experienced tumor stabilization."
      - "CT-2584 trial in the United Kingdom, we have
      treated more than 50 patients, 35 of whom were evaluable for tumor response
      to CT-2584. It is exciting that 10 (29%) of these patients' cancers
      stabilized on CT-2584, and that seven are still alive after a median of 10
      months following treatment. Overall survival for all 35 evaluable patients
      in both trials is also very encouraging with 21 alive a median of 10 months
      after starting treatment with CT-2584."
      ------------------------------------------------------------------------
      CGS27023A
      - Novartis East Hanover, N.J.
      - Phase I
      Mechanism: Prevent new blood vessels from invading
      surrounding tissue; Synthetic inhibitor of matrixmetalloproteinases (MMPs)
      ------------------------------------------------------------------------
      ZD0101
      - Zeneca Pharmaceuticals Wilmington, Del.
      - Phases I and II
      Mechanism: Targeted Anti-vascular therapy; Bacterial toxin that binds
      to new blood vessels and induces inflammatory response
      ------------------------------------------------------------------------
      IM862
      - Cytran Kirkland, Wash.
      - Phase II against Kaposi's Sarcoma
      Mechanism: Unknown
      ------------------------------------------------------------------------
      PRECLINICAL THERAPIES
      ----------------------------------------
      ANGIOSTATIN Protein
      For: CANCER!
      PHASE: PreClinical, EntreMed
      Other:
      "..a 38 kD protein of uncertain origin, inhibits endothelial cell
      proliferation."

      "A protein that attacks cancer by blocking blood vessel
      formation can be administered using a modified gene contained in a
      non-infective virus, according to a French study involving laboratory mice."
      - Third generation of inhibitors (most promising, the BIG GUN)
      ---------------------------------
      ENDOSTATIN Protein
      For: CANCER!
      PHASE: PreClinical, EntreMed
      Other:
      "Endostatin protein is believed to be one of the most effective
      antiangiogenic compounds in EntreMed's arsenal."
      - Third generation of inhibitors (THE BIGGEST GUN)
      ---------------------------------
      2-Methoxyestraidol (2-ME2)
      For: CANCER!
      PHASE: PreClinical, EntreMed
      Other:
      - "2-ME2 could be significant because of TWO reasons it is a natural
      estrogen metabolite, that appears to not only inhibit angiogenesis but to
      KILL cancer cells as well."
      - "2-ME2 acts a lot like Taxol"
      - Third generation of inhibitors
      ---------------------------------
      VASCULOSTATIN
      For: ?
      PHASE: PreClinical, EntreMed
      ------------------------------------------------------------------------
      OTHERS WHERE PEOPLE TOSS THEM OUT WITHOUT
      BACKING THEM UP:
      ------------------------------------------------------------------------
      ????
      For:
      PHASE:
      From: Angstrom
      Other:
      ------------------------------------------------------------------------
      TROPONIN
      For:
      PHASE:
      From: BLSI
      Other:

      ==================================
      This post dedicated to Moses Judah Folkman, the 'Father of Angiogenesis'
      who persevered despite all his critics. A second dedication to his wife
      Paula of 38 years.

      "I would come home at night so disheartened and she would ask, 'Why do you
      care what they think?' She has always been very supportive."
      - M. Judah Folkman

      Does Folkman believe that he will eventually cure cancer?
      "No, I don't think angiogenesis inhibitors will be the cure for cancer," he
      answers. "But I do think that they will make cancer more survivable and
      controllable, especially in conjunction with radiation, chemotherapy, and
      other treatments. I am very excited to see how they will work in people."

      (Excerpts from Scientific American, pg 34, October 1998)