Hormones, Receptors, and Signal Transduction

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					Hormones, Receptors, and Signal
         Transduction

           MCB 720

        March 2, 2010


  John J. Kopchick, Ph.D.
   Hormone -Receptor
      Interactions

Hormone stems from a Greek term
      meaning “to spur on.”
 General        Higher organisms, from the fruit fly to
                     humans, are comprised of cells.
principles
                The cells often unite to form tissue
                     which come together to form organs
                     which together make up the
                     organism.
                Cells of an organism do not live in
                     isolation.
                The communication between cells
                     ultimately controls growth,
                     differentiation, and metabolic
                     processes within the organism.
                Communication between cells is often by
                     direct cell to cell contact.
                Communication frequently occurs
                     between cells over short and long
                     distances.
General principles cont...
   In cases of short and long distance
        communication, a substance may be released
        by one cell and recognized by a different
        target cell.
   In the target cell, a specific response is
        induced.
   Cells use an amazing number of signaling
        chemicals.
   These signaling molecules are termed
       “hormones.”
   The ability of a hormone to induce a response in
       a target cell is usually mediated by a
       hormone receptor on, or in, the target cell.
           General characteristics
                of hormones
   Hormones are molecules synthesized by specific
       tissue. Classically these tissue were called
       glands.
   Hormones are secreted directly into the blood
       which carries them to their sites of action.
   Hormones are present at very low levels in the
       circulatory system.
   Hormones specifically affect or alter the
       activities of the responsive tissue (target
       tissue).
   Hormones act specifically via receptors located
       on, or in, target tissue.
Hormone/Receptor Interaction
     Secondary Signals
           Hormone      Receptor      Mediator     Effectors
                                      Protein


Range of     H1            R1           G1           E1
possible
pathways
             H2            R2           G2           E2

   Possible pathways of transmission of hormonal signal. Each
   hormone can work through one or more receptors; each
   hormone-receptor complex can work through one or more
   mediator proteins (either G proteins or other signaling
   mechanism), and each mediating protein or enzyme activated
   by hormone-receptor complexes can affect one or more
   effectors functions.
The four primary arenas
    of hormone action
Reproduction              Growth &
                          Development




               Hormones



Maintenance of        Energy production,
internal              utilization &
environment           storage
                       Definitions
Endocrine - Refers to the internal secretion of biologically
          active substances.
Exocrine - Refers to secretion outside the body, for
          example, through sweat glands, mammary
          glands, or ducts lead to the gastrointestinal.
Hormone - Substances released by an endocrine gland and
          transported through the bloodstream to
          another tissue where it acts to regulate
          functions in the target tissue (classic
          definition).
       Paracrine - Hormones that act locally on cells that did
            not produce them.
       Autocrine - Hormones that act on cells that produced
            them.
Receptors -Hormones bind to receptors molecules on cells.
            A receptor must specifically recognize the
            hormone from the numerous other molecules in
            the blood and transmit the hormone binding
            information into a cellular specific action.
 Endocrine                                            Blood vessel



  Hormone secretion
  into blood by                    Distant target cells
  endocrine gland


                                                          Paracrine

                  Secretory cell    Adjacent target cell


Autocrine                                       Receptor
                                                Hormone or other extra
                                                cellular signal


            Target sites on same cell
    Actions of hormones &
   neurotransmitters & their
       interrelationships
(H,hormone; R, receptor; N,neurotransmitter.)
Examples of Hormones and
glands that produce them
                Selected hormones & their functions

  Hormone                Source                   Principal functions
Insulin              Pancreas        Controls blood-sugar level and storage of glycogen.

Glucagon             Pancreas        Stimulates conversion of glycogen to glucose; raises
                                            blood sugar level.

Oxytocin             Pituitary gland Stimulates contraction of the uterine muscles and
                                            secretion of milk by the mammary glands.

Vasopressin          Pituitary gland Controls water excretion by the kidneys; stimulates
                                            contraction of the blood vessels.

Growth hormone       Pituitary gland Stimulates growth.

Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex, which,in turn,releases
hormone (ACTH)                          several steroid hormones.

Prolactin            Pituitary gland Stimulates milk production by the mammary glands
                                            after birth of baby.

Epinephrine         Adrenal glands   Stimulates rise in blood pressure, acceleration of
                                            heartbeat, decreased secretion of insulin, and
                                            increased blood sugar.
          Selected hormones & their functions cont...
  Hormone             Source                  Principal functions
Cortisone          Adrenal glands    Helps control carbohydrate metabolism, salt
                                           and water balance, formation and storage of
                                           glycogen.
Thyroxine &        Thyroid gland     Increases the metabolic rate of carbohydrates
Triiodothyronine                           and proteins.

Calcitonin         Thyroid gland     Prevents the rise of calcium and phosphate in the
                                          body.
Parathyroid        Parathyroid gland Regulates the metabolism of calcium and
                                           phosphate in hormone in the body.

Gastrin            Stomach            Stimulates secretion of gastric juice.

Secretin           Duodenum          Stimulates secretion of pancreatic juice.
Estrogen           Ovaries           Stimulates development and maintenance of
                                               female sexual characteristics.
Progesterone       Ovaries           Stimulates female sexual characteristics and
                                               maintains pregnancy.
Testosterone       Testes             Stimulates development and maintenance of male
                                              sexual characteristics.
    “Generic”
Hormone/Receptor
  Interactions
Regulation of transcription by hormones that act on
                  the cell surface.



                                         M odification
H      H R      2nd
                                             F
                M essenger                                PP


                        Effector
                                                  Pre-mRNA

             Response
                                   Protein               mRNA
       Types of Hormones
 Catecholamines           and Thyroid
 Hormones
     Small and derived from amino acids (epinephrine,
 thryoxine.)

 Steroid     Hormones and Vitamin D
     Relatively small and derived from cholesterol

 Prostaglandin's
     Relatively small and derived from fatty acids

 Proteins     or Polypeptides
     relatively large and derived from translation of hormone
     specific mRNA (growth hormone, insulin)
               Thyroid Hormones
   Synthesized solely in the thyroid gland ( T4; 3’,5’,3,5-L-
    tetra-iodothyronine).
   Majority of the active form, T3 (3’,3,5-L-tri-
    iodothyronine), is produced in the peripheral tissues
    through deiodination of T4.
   Thyroid gland cells concentrates iodine for thyroid
    hormone synthesis.
   Iodine is attached to tyrosine residues on a protein,
    termed thyroglobulin. Tyrosine residues are then
    coupled together to yield thyronines.
   Proteolytic digestion of thyroglobulin then yields T4 and
    T3 in a 10:1 ratio.
   Helps in the metabolism of sugars.
   The half life of T4 is 7 days and that of T3 is 1 day.
         Tyroxine [Tetra-iodothyronine (T4)]

     I              I
                                      NH3+

HO              O               CH2    C      COO -
                                       H
                                                        Thyroid
     I              I                                   Hormones

                        Tri-iodothyronine (T3)        Increase of
                                                      oxidation of sugars
     I              I                                 by most body cells;
                                      NH3+            induction of some
                                                      enzymes
HO              O               CH2   C      COO -
                                      H

                    I
                                  T3
T4
      T3
                                 R           T3
                                F F          R       F       PP
                        T4


     PB                                 T3
                        T3
                                                  Pre-mRNA

                    Response
                                  Protein             mRNA




      Regulation of transcription by thyroid hormones. T3
      and T4 are tri-iodotyronine and tyroxine,
      respectively.
              Steroid Hormones
   Produced in the adrenals, ovaries, testes, and
    placenta.
   Derived from cholesterol.
   Enzymes in the various glands control the final
    product. For example, cytochrome P450c11 which is
    located in the adrencortical cells, is involved in
    coritsol production. This enzyme is lacking in the
    gonads, that do not produce cortisol or aldosterone.
   Gonads, however, can produce
    dihydroxytestosterone, estradiol, or
    progesterone depending upon the enzymes present in
    the gonadal tissue.
   Over 50 different steroid metabolites have been
    described.
Cholesterol Metabolism
Steroid Hormones
                                  S     S
 S                 R HSP                            S   S
          S          HSP          F    F            R   R       PP


 S      HSP    S       S               S        S       HSP
PB             R       R               R        R       HSP
        HSP


                                                            pre-mRNA
                              S             R HSP
                                              HSP

                   Response
                                      Protein           mRNA


     Regulation of transcription by steroid hormones
                Catecholamines
   Are synthesized in nervous tissues from which the
    adrenal medulla is derived.
   Adrenal medulla is the major source for circulating
    epinephrine.
   Synthesized from tyrosine which is converted to
    dihydroxyphenylalanine (DOPA) by tyrosine
    hydroxylases.
   Subsequent conversions to dopamine and then to nor
    epinephrine which is released by most catecholamine-
    producing cells of the body.
   In the adrenal medulla and a few other tissue, nor
    epinephrine is converted to epinephrine.
   The half life is 1-2 minutes.
                                    Flight, fright, or fight!
     Prostaglandins and Leukotrienes

   They can be produced by most cells depending upon lipid
    and enzyme content of the cells.
   Arachidonic acid, which is derived from lipid metabolism,
    is the precursor compound.
   Depending upon the lipoxygenase present in the cell,
    either, HETE, prostaglandin (G2) or leukotrienes
   Cyclooxygenase (involved in PGG2 synthesis) is widely
    distributed throughout the body and is inhibited by
    aspirin, indomethacin, and other nonsteroidal and anti-
    inflammatory agents.
            Several COX inhibitors!! - Problems
   The half-life is a few seconds.
Hormone Antagonists
Examples of hormone antagonists used in therapy
Antagonist to           Use
Growth Hormone Acromegaly, Diabetes
Progesterone       Contraceptive, abortion
Glucocorticoid     Spontaneous Cushing’s
   Syndrome
Mineralo-corticoid Primary and secondary
                   mineralocorticoid excess
Androgen           Prostate cancer
Estrogen           Breast cancer             Tamoxifin
GnRH               Prostate cancer
 -Adrenrgic       Hypertension, hyperthyroidism
Prostaglandin      Acute and chronic inflammatory
                   disease
Hormone Receptors
        and

Signal Transduction
     Hormone Receptors
Nuclear receptors
    estrogens

                Cytoplasmic receptors
            Most steroid and thyroid hormones


                              Cell surface membrane
                                      receptors
                                Polypeptide hormones and
                                     catecholamines
                                            Hormone    Membrane
             Plasma                                    Effects
             Membrane


                                      Receptor
                                      Effector
            Cellular
            Trafficking

                Enzymes          Secondary Messenger
                                 or Secondary Signal

           Activated Inhibited
                                                       Protein
                                                       Synthesis
                                  DNA Synthesis
                   Nucleus        RNA Synthesis

A general model for the action of peptide hormones, catecholamines, and
other membrane-active hormones. The hormone in the extra cellular fluid
binds to the receptor and activates associated effector(s) systems, that
may or may not be in the same molecule. This activation results in
generation of an intracellular signal or second messenger that, through a
variety of common and branched pathways, produces the final effects of
the hormone on metabolic enzyme activity, protein synthesis, or cellular
growth and differentiation.
Receptors that span the
 membrane Seven times
       cAMP: synthesis and degradation

cAMP
cAMP
     Amino acid Phosphorylation is very
      important in intracellular signal
               transduction

            ATP
             ATP




                                             S Serine
 Protein Kinases – transfer terminal Phosphate groups
       from ATP to Serine, Threonine, or Tyrosine residues
       in proteins
Result in activation or inactivation of the recipient protein !
S Serine
               Amino acids
               that can be
              phosphorylated

 Threonine




 Y Tyrosine
Peptide hormone receptors
Huising, et.al.
J. Endo. 2006. 189:1-25
General View
     of
 Metabolism
    Levels of blood sugar
(glucose) regulate secretion
      of hormones from
         the pancreas

     Pancreas secretes
    insulin when glucose
       levels are high

       Insulin binds to
    insulin receptors on
    fat and muscle and
     “promotes” glucose
            uptake

Overall effect: blood glucose
   levels return to normal
Glucose Tolerance Test
     The Insulin Receptor

 Responsible for clearance of glucose
 In addition to binding insulin, it
  possesses a tyrosine kinase activity
 It is involved in many cellular
  activities
Glucose Transporter Intracellular Trafficking
           Insulin Receptor




Tyrosine
kinase
 Insulin-mediated glucose transport signaling pathway
  Insulin-mediated glucose transport signaling pathway
                                                 Insulin


                               IR
                                     a       a
                                            
Cell membrane




                                             P
                         IRS
                               PI3K



                Glut4          Akt
                                         P




                                                           Xiao Chen, 2006
Insulin-mediated glucose transport signaling pathway
 Insulin-mediated glucose transport signaling pathway


                              IR        Insulin
   glucose                          a       a
                                                Cell membrane




                                            P
                        IRS
                              PI3K



                              Akt
                                        P




                                                       Xiao Chen, 2006
Expectancy; Low = 73.6; High =
                         Time, Nov, 2006
Obesity is a Global Pandemic Disease
 USA Today
Feb. 9, 2010
 USA Today
Feb. 9, 2010
               Reduce




 USA Today
Feb. 9, 2010
41 grams
Expectancy; Low = 73.6; High =
                         Time, Nov, 2006
               Insulin Signaling Pathways by C. Hooper
http://www.abcam.com/index.html?pageconfig=resource&rid=10602&pid=7
Cartoon of Intracellular Signaling System Used By
   Many Peptide Hormones and Growth Factors


l   For example
    – Insulin
    – EGF
Tyrosine kinase receptors are a family of receptors with a similar
structure. They each have a tyrosine kinase domain (which
phosphorylates proteins on tyrosine residues), a hormone binding
domain, and a carboxyl terminal segment with multiple tyrosines for
autophosphorylation. When hormone binds to the extra cellular domain
the receptors aggregate.
When the receptors aggregate, the tyrosine kinase domains
phosphorylate the C terminal tyrosine residues.
This   phosphorylation produces binding sites for proteins
with   SH2 domains. GRB2 is one of these proteins. GRB2,
with   SOS bound to it, then binds to the receptor complex.
This   causes the activation of SOS.
SOS is a guanyl nucleotide-release protein (GNRP). When this
is activated, it causes certain G proteins to release GDP and
exchange it for GTP. Ras is one of these proteins. When ras
has GTP bound to it, it becomes active.
Activated ras then causes the activation of a cellular kinase
called raf-1.
Raf-1 kinase then phosphorylates another cellular kinase called
MEK. This cause the activation of MEK.
Activated MEK then phosphorylates another protein kinase called MAPK
causing its activation. This series of phosphylating activations is called
a kinase cascade. It results in amplification of the signal.
                                      Adapted from: Dr. Donald F. Slish,
                                        Biological Sciences Department,
                                  Plattsburgh State University, Plattsburgh,
                                                       NY.




Among the final targets of the kinase cascade are transcriptions factors (fos
and jun showed here). Phosphorylation of these proteins causes them to
become active and bind to the DNA, causing changes in gene transcription.
   Examples of therapeutics
developed based on these types
of receptors and the associated
tyrosine kinase signaling system


          Erbitux – Imclone
        Iressa - AstraZeneca
         Gleevec – Novartis
       Herceptin - Genentech
EGF Receptor Signal Transduction Pathway
                                           SIGMA-ALDRICH

                                      Tyrosine kinase




                 Cell Proliferation
           Epidermal Growth Factor Receptor

                       EGF


Cysteine
                       Receptor
 Rich                                        EGF
Domain                Dimerization



                                                          Cell
                                                        Membrane

 Tyrosine                                           *
                                     *
  Kinase                             *              *
  Domain                             *              *
                                            P P
                                            Signal
                                         Transduction
              EGFR Family
   The epidermal
    growth factor
    (EGF) family of
    receptor tyrosine
    kinases consists of
    four receptors,
   ErbB1 (EGFR)
   ErbB2 (Her/Neu)
   ErbB3 (HER3)
   ErbB4 (HER4).
      Non-small cell lung cancer
   Non-small cell lung cancer comprises over
    75% of all lung cancers. In 2006, more
    than 338,000 cases of the disease are
    expected to be diagnosed in the seven
    major pharmaceutical markets. High unmet
    needs of therapy still persist for this
    tumor type. The overall survival of NSCLC
    patients remains below 12 months.
   The EGfR is expressed on these
    cells.
        Epidermal Growth Factor Receptor in Non–Small-Cell Lung Carcinomas:
    Correlation Between Gene Copy Number and Protein Expression and Impact on
                                    Prognosis
    Fred R. Hirsch, Marileila Varella-Garcia, Paul A. Bunn, Jr, Michael V. Di Maria, Robert Veve, Roy M.
                           Bremnes, Anna E. Barón, Chan Zeng, Wilbur A. Franklin
                        Journal of Clinical Oncology, Vol 21, 2003: 3798-3807, 2003



• The percentage of EGFR
  positive tumor cells per slide
  (0% to 100%) was multiplied
  by the dominant intensity
  pattern of staining (1,
  negative or trace; 2, weak; 3,
  moderate; 4, intense);
  therefore, the overall score
  ranged from 0 to 400 (Fig 1).
  Specimens with scores 0 to
  200, 201 to 300, and 301 to
  400 were respectively
  classified as having negative
  or low, intermediate, and
  high levels of expression.
Influence of histological type, smoking history and chemotherapy on survival
after first-line therapy in patients with advanced non-small cell lung cancer

        Itaya , Yamaoto, Ando, Ebisawa, Nakamura, Murakami, Asai, Endo and Takahashi
                                       Cancer Science
                                  Volume 98, Page 226, 2007



  • For overall survival,
    smoking history and
    histology were
    significant
    prognostic factors.
    The 2-year overall
    survival rates were
    as follows: smokers,
    17%; non-smokers,
    52%, P < 0.0001;
     Iressa (gefitinib tablets)
                  AstraZeneca.

IRESSA is indicated as
   monotherapy for the
 continued treatment of
   patients with locally
 advanced or metastatic
    non-small cell lung
  cancer after failure of
 both platinum-based and
        docetaxel
 chemotherapies who are
    benefiting or have
     benefited from
         IRESSA.
          Iressa (gefitinib tablets)
                             AstraZeneca.
• Mechanism of Action

•   The mechanism of the clinical
    antitumor action of gefitinib is
    not fully characterized.

•   Gefitinib inhibits the
    intracellular phosphorylation of
    numerous tyrosine kinases
    associated with transmembrane
    cell surface receptors, including
    the tyrosine kinases associated     Gefitinib is an anilinoquinazoline
    with the epidermal growth             with the chemical name 4-
    factor receptor (EGFR-TK).
                                        Quinazolinamine, N-(3-chloro-
•   EGFR is expressed on the cell       4- fluorophenyl) -7-methoxy-
    surface of many normal cells and     6- [3-4-morpholin) propoxy]
    cancer cells. No clinical studies
    have been performed that                     C22H24ClFN4O3
    demonstrate a correlation
    between EGFR receptor
    expression and response to
    gefitinib.
                                Zactima
     Tyrosine Kinase Inhibitor for Treatment of
                    Lung Cancer
 •   Zactima (ZD6474) is an orally available Tyrosine Kinase Inhibitor (TKI)
     under development by AstraZeneca for the treatment of solid tumours.
     Following promising results in early clinical trials, Zactima has now
     progressed to phase III development in Non-Small Cell Lung Cancer
     (NSCLC), its primary indication.
 •   If phase III trials prove successful, analysts believe Zactima could be
     on the market by 2008 and help to fill the void left by recent setbacks
     with Iressa (gefitinib), its first TKI for lung cancer.
 •   At the beginning of the year, AstraZeneca withdrew its marketing
     application for Iressa in Europe. This followed the release of new long-
     term data that showed it to be no better than placebo in prolonging
     patients' lives.
 •   Meanwhile, in the US Iressa will soon be available only to existing
     NSCLC patients who have already shown treatment benefit and will not
     be prescribed to new patients. While Iressa has stalled in Europe and
     the US, it is approved in more than 30 countries elsewhere.



http://www.drugdevelopment-technology.com/projects/zactima/ AstraZeneca
                              BCR - ABL
•   The exact chromosomal defect in Philadelphia chromosome is
    translocation. Parts of two chromosomes, 9 and 22, swap places. The result
    is that part of the BCR ("breakpoint cluster region") gene from chromosome
    22 (region q11) is fused with part of the ABL gene on chromosome 9 (region
    q34). Abl stands for "Abelson", the name of a leukemia virus which carries a
    similar protein.
•   The result of the translocation is a protein of p210 or sometimes p185
    weight (p is a weight fraction of cellular proteins in kDa). The fused "bcr-abl"
    gene is located on the resulting, shorter chromosome 22. Because abl
    carries a domain that can add phosphate groups to tyrosine residues
    (tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although
    the bcr region is also a serine/threonine kinase, the tyrosine kinase function
    is very relevant for therapy, as will be shown.)
•   The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor
    subunit. The bcr-abl transcript is constitutively active, i.e. it does not require
    activation by other cellular messaging proteins. In turn, bcr-abl activates a
    number of cell cycle-controlling proteins and enzymes, speeding up cell
    division. Moreover, it inhibits DNA repair, causing genomic instability and
    potentially causing the feared blast crisis in CML.
                                         BCR-ABL
•   The exact chromosomal defect in Philadelphia chromosome is translocation. Parts of two
    chromosomes, 9 and 22, swap places. The result is that part of the BCR ("breakpoint cluster
    region") gene from chromosome 22 (region q11) is fused with part of the ABL gene on
    chromosome 9 (region q34). Abl stands for "Abelson", the name of a leukemia virus which carries
    a similar protein.
•   The result of the translocation is a protein of p210 or sometimes p185 weight (p is a weight
    fraction of cellular proteins in kDa). The fused "bcr-abl" gene is located on the resulting, shorter
    chromosome 22. Because abl carries a domain that can add phosphate groups to tyrosine
    residues (tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although the bcr
    region is also a serine/threonine kinase, the tyrosine kinase function is very relevant for therapy,
    as will be shown.)
•   The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl
    transcript is constitutively active, i.e. it does not require activation by other cellular messaging
    proteins. In turn, bcr-abl activates a number of cell cycle-controlling proteins and enzymes,
    speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and
    potentially causing the feared blast crisis in CML. (Chronic myelogenous leukemia)
                      Gleevec
(imatinib mesylate, aka STI-571)




      FDA APPROVES GLEEVEC FOR LEUKEMIA TREATMENT

 The Food and Drug Administration today announced the approval of
Gleevec (imatinib mesylate, also known as STI-571), a promising new
oral treatment for patients with chronic myeloid leukemia (CML) -- a
 rare life-threatening form of cancer. FDA reviewed the marketing
      application for Gleevec in less than three months under its
                   "accelerated approval" regulations.

                         Novartis, May 10, 2001

   Used in the treatment of Chronic Myeloid Leukemia (CML) and
              Gastrointestinal Stromal Tumors (GIST)
Mechanism of Action                           Gleevec         (Novarits)

Imatinib mesylate is a protein-tyrosine
kinase inhibitor that inhibits the Bcr-Abl
tyrosine kinase, the constitutive
abnormal tyrosine kinase created by the
Philadelphia chromosome abnormality in
chronic myeloid leukemia (CML). It
inhibits proliferation and induces
apoptosis in Bcr-Abl positive cell lines as
well as fresh leukemic cells from
Philadelphia chromosome positive chronic       In vitro studies
myeloid leukemia. In colony formation          demonstrate imatinib is
assays using ex vivo peripheral blood and      not entirely selective; it
bone marrow samples, imatinib shows            also inhibits the receptor
inhibition of Bcr-Abl positive colonies        tyrosine kinases for
from CML patients. In vivo, it inhibits        platelet-derived growth
tumor growth of Bcr-Abl transfected            factor (PDGF) and stem
murine myeloid cells as well as Bcr-Abl        cell factor (SCF), c-Kit,
positive leukemia lines derived from CML       and inhibits PDGF
patients in blast crisis.                      mediated cellular events
Monoclonal Antibody Therapy
Antibody to EGF R binds and blocks EGF from binding

                               EGF




                                 Erbitux, Imclone


                                                 Cell
                                               Membrane

 Tyrosine
  Kinase
                       Therefore, no tyrosine kinase
  Domain
                               activity and
                         no intracellular signaling
                    Herceptin

   is the first humanized antibody approved for the
treatment of HER2-positive metastatic breast cancer.
Herceptin is designed to target and block the function
            of HER2 protein over expression.
                       Genentech




   HER 2 = Human Epidermal Growth Factor
                Receptor 2
       Herceptin,
  a monoclonal antibody,
      binds to HER2
  and ultimately results
in destruction of the cell
So two targets to inhibit EGF/EGFR signaling
                 EGF

   1
                 Receptor
                                   EGF
                Dimerization



                                                    Cell
                                                  Membrane

Tyrosine
 Kinase
 Domain
                                  P P
                                              2
                                  Signal
                               Transduction   Colored slide: D-88
                             Diabetes

Diabetes - from the Greek word, diabetes, meaning “a
crossing over or passing through”. Any of several metabolic
disorders marked by excessive discharge of urine and
persistent thirst. (The American Heritage Dictionary).


Diabetes mellitus - a chronic disease of pancreatic origin,
characterized by insulin deficiency, subsequent inability to utilize
carbohydrates, excess sugar in the blood and urine, excessive thirst,
hunger, and urination, weakness, emaciation, imperfect combustion of
fats resulting in acidosis, and, without injection of insulin, results in
coma and death. (The American Heritage Dictionary).
            Diabetes, con’t.
   Type I or Insulin Dependent Diabetes
    Mellitus (IDDM) – Also called juvenile
    diabetes - lack of insulin

   Type II or Non Insulin Dependent
    Diabetes Mellitus (NIDDM) – Also called
    adult onset diabetes - insulin present but
    cells do not respond that is they
    are“insulin resistant”.
    Facts: (Diabetes 1996 Vital Statistics, ADA)

16-20 million Americans have diabetes.

385,000 diabetes die each year.

625,000 new cases each year.

Every minute of every day, someone new is diagnosed with
   diabetes.

127,000 children (younger that age 20) have diabetes.

11% of the U.S. population, age 65-74, has diabetes.
               Diabetes, con’t.

Diabetic eye disease (retinopathy): by 15 years after
      diagnosis of diabetes, retinopathy is present in
      97% of insulin users and 80% of non-insulin users.


About 20% of people with diabetes have kidney
      disease (nephropathy).


40% of the deaths associated with diabetes are due to
     heart disease.
                      Types of diabetes mellitus
                   (Diabetes 1996 Vital Statistics, ADA)

Type I or insulin-dependent diabetes mellitus (IDDM) - Low
or absent levels of endogenous insulin. Dependent on insulin therapy to
prevent ketoacidosis and sustain life. Onset predominantly before age 30
but can occur at any age. Onset is usually abrupt and patients are usually
thin. Cause appears to be a combination of genetic and environmental
determinants. Pancreatic islet cells are destroyed.

Type II or non-insulin dependent diabetes mellitus
(NIDDM) - Normal to High insulin levels characterize most patients,
indicating insulin resistance in tissues. Often see development of low
insulin levels as the disease progresses. Patients are not prone to
ketoacidosis during normal circumstances. Although not dependent on
insulin therapy for survival, many require it for adequate blood glucose
control. Onset is predominantly after age 40, particularly in whites,
and often asymptomatic; most patients are obese. Cause appears to be a
combination of genetic and environmental lifestyle determinants. Drugs
are available to promote insulin release from the pancreas or to allow
cells to be more sensitive to insulin action.
              Types of diabetes, con’t.
Gestational Diabetes Mellitus (GDM) - Glucose intolerance that has its
onset or recognition during pregnancy. Associated with older age, obesity,
and family history of diabetes. Risk for subsequent NIDDM is increased.
Newborn offspring often have macrosomia and may also be at increased
risk for developing NIDDM.


Diabetes insipidus - Caused by the total or partial lack of the hormone
vasopressin, also called antidiuretic hormone. Blood glucose is normal, but
increased urine output with accompanying thirst.


Other types of diabetes - Diabetes secondary to other conditions with
hyperglycemia at a level diagnostic of diabetes.


Impaired Glucose Tolerance (IGT) - Blood glucose levels that are higher
than normal but not diagnostic for diabetes mellitus. Risk for subsequent
NIDDM is increased.

				
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