hormones, receptors, and signal transduction
TRANSCRIPT
Hormones, Receptors, and Hormones, Receptors, and Signal TransductionSignal Transduction
MCB 720MCB 720
March 2, 2010March 2, 2010
John J. Kopchick, Ph.D.John J. Kopchick, Ph.D.
Hormone -Receptor Hormone -Receptor InteractionsInteractions
HormoneHormone stems from a stems from a Greek Greek term term meaningmeaning ““to spur onto spur on.”.”
General General principlesprinciples
Higher organisms, from the fruit fly to Higher organisms, from the fruit fly to humans, are comprised of humans, are comprised of
cells.cells. The The cells cells often unite to form often unite to form tissuetissue
which come together to form which come together to form organsorgans which together make up which together make up the the organismorganism..
Cells of an Cells of an organismorganism do not live in do not live inisolation.isolation.
TheThe communicationcommunication between cells between cells ultimately controls growth, ultimately controls growth,
differentiation, and metabolic differentiation, and metabolic processes within the organism.processes within the organism.
CommunicationCommunication between cells is between cells is often by often by direct cell to cell contact.direct cell to cell contact.
CommunicationCommunication frequently occurs frequently occurs between cells over between cells over shortshort and and
long long distances.distances.
General principles contGeneral principles cont...... In cases of short and long distance In cases of short and long distance
communication, a substance may be communication, a substance may be releasedreleased by one cell and recognized by a by one cell and recognized by a different different targettarget cell.cell.
In the target cell, a In the target cell, a specificspecific response is response is induced.induced.
Cells use an amazing number of Cells use an amazing number of signalingsignaling chemicals. chemicals.
These signaling molecules are termed These signaling molecules are termed ““hormoneshormones.”.”
The ability of a The ability of a hormonehormone to to induce induce a a response in response in a a targettarget cell is usually cell is usually mediated by a mediated by a hormone hormone receptorreceptor on, or on, or in, the target cell.in, the target cell.
General characteristicsGeneral characteristicsof hormonesof hormones
Hormones are molecules synthesized by Hormones are molecules synthesized by specific specific tissue. Classically these tissue tissue. Classically these tissue were called were called glandsglands..
Hormones are secreted directly into the Hormones are secreted directly into the blood blood which which carriescarries them to their sites them to their sites of action.of action.
Hormones are present at very Hormones are present at very lowlow levels in levels in the the circulatory system.circulatory system.
Hormones specifically affect or alter the Hormones specifically affect or alter the activities of the responsive tissue activities of the responsive tissue
((targettarget tissue).tissue). Hormones act specifically via Hormones act specifically via receptorsreceptors
located located on, or in, on, or in, targettarget tissue. tissue.
Hormone/Receptor InteractionHormone/Receptor InteractionSecondary SignalsSecondary Signals
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.
HH11 RR11 GG11 EE11Range of possible pathways
HormoneHormone ReceptorReceptor Mediator Mediator ProteinProtein
EffectorsEffectors
HH22 RR22 GG22 EE22
Hormones
Reproduction
Growth & Development
Maintenance of internal environment
Energy production, utilization & storage
The four primary arenasThe four primary arenas of hormone action of hormone action
DefinitionsDefinitionsEndocrineEndocrine -- Refers to the internal secretion Refers to the internal secretion
of biologically active substances.of biologically active substances.ExocrineExocrine - - Refers to secretion outside the body, for Refers to secretion outside the body, for
example, through sweat glands, mammary example, through sweat glands, mammary glands, or ducts lead to the gastrointestinal.glands, or ducts lead to the gastrointestinal.
HormoneHormone - - Substances released by an endocrine Substances released by an endocrine gland and transported through the gland and transported through the bloodstream to another tissue where it acts bloodstream to another tissue where it acts to regulate functions in the target tissue to regulate functions in the target tissue (classic definition).(classic definition).
ParacrineParacrine - Hormones that act locally on cells that - Hormones that act locally on cells that did not produce them.did not produce them.
AutocrineAutocrine - Hormones that act on cells that - Hormones that act on cells that produced them.produced them.
ReceptorsReceptors --Hormones bind to receptors molecules on Hormones bind to receptors molecules on cells. A receptor must specifically recognize cells. A receptor must specifically recognize the hormone from the numerous other the hormone from the numerous other molecules in the blood and transmit the molecules in the blood and transmit the hormone binding information into a cellular hormone binding information into a cellular specific action.specific action.
EndocrinEndocrinee
Blood vesselBlood vessel
Distant target Distant target cellscells
Hormone Hormone secretion into secretion into blood by blood by endocrine glandendocrine gland
ParacriParacrinene
Secretory Secretory cellcell
Adjacent target cellAdjacent target cell
AutocrinAutocrinee
Target sites on same cellTarget sites on same cell
ReceptorReceptorHormone or other Hormone or other extra cellular signalextra cellular signal
H HHH
H
HR HR
HR HR
H
H
HH
H H R
NN
H
HR R
RH
NN
NN
H H
Endocrine cell Neurotransmitter cell
Autocrine
Paracrine
AutocrineBloodvessel
Axon
Neurotransmitter &hormone target cell(H,hormone; R, receptor; N,neurotransmitter.)(H,hormone; R, receptor; N,neurotransmitter.)
Actions of hormones & Actions of hormones & neurotransmitters & their neurotransmitters & their
interrelationshipsinterrelationships
Examples of Hormones Examples of Hormones and glands that and glands that produce themproduce them
Selected hormones & their functionsSelected hormones & their 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.
HormoneHormone SourcSourcee
PrincipalPrincipal functionsfunctions
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.
HormoneHormone SourcSourcee
Principal Principal functionsfunctions
Selected hormones & their functions cont...Selected hormones & their functions cont...
““Generic”Generic”Hormone/Receptor Hormone/Receptor
Interactions Interactions
H R F PP2ndMessenger
Effector
Response
Protein mRNA
Pre-mRNA
ModificationH
Regulation of transcription by hormones that act on the cell surface.
Types of HormonesTypes of Hormones Catecholamines and Thyroid Catecholamines and Thyroid
HormonesHormonesSmall and derived from amino acids (epinephrine, Small and derived from amino acids (epinephrine,
thryoxine.)thryoxine.) Steroid Hormones and Vitamin DSteroid Hormones and Vitamin D
Relatively small and derived from cholesterolRelatively small and derived from cholesterol Prostaglandin'sProstaglandin's
Relatively small and derived from fatty acidsRelatively small and derived from fatty acids Proteins or PolypeptidesProteins or Polypeptides
relatively large and derived from translation of relatively large and derived from translation of hormone hormone specific mRNA (growth hormone, insulin)specific mRNA (growth hormone, insulin)
Thyroid HormonesThyroid Hormones Synthesized solely in the Synthesized solely in the thyroidthyroid gland ( gland ( T4T4; ;
3’,5’,3,5-L-tetra-iodothyronine).3’,5’,3,5-L-tetra-iodothyronine). Majority of the active form, Majority of the active form, T3T3 (3’,3,5-L-tri- (3’,3,5-L-tri-
iodothyronine), is produced in the peripheral tissues iodothyronine), is produced in the peripheral tissues through deiodination of through deiodination of T4T4..
Thyroid gland cells concentrates Thyroid gland cells concentrates iodineiodine for thyroid for thyroid hormone synthesis.hormone synthesis.
IodineIodine is attached to is attached to tyrosinetyrosine residues on a residues on a protein, termed thyroglobulin. Tyrosine residues protein, termed thyroglobulin. Tyrosine residues are then coupled together to yield are then coupled together to yield thyroninesthyronines..
Proteolytic digestion of thyroglobulin then yields Proteolytic digestion of thyroglobulin then yields T4T4 and and T3T3 in a in a 10:110:1 ratio. ratio.
Helps in the metabolism of Helps in the metabolism of sugarssugars.. The half life of T4 is The half life of T4 is 7 days7 days and that of T3 is and that of T3 is 1 day.1 day.
HOHO
II
II
II
II II
II
II
OO
OO CHCH22 CCHH
NHNH33++
COO COO --
CHCH22 CCHH
NHNH33++
COO COO --
Tyroxine [Tetra-iodothyronine (T4)]Tyroxine [Tetra-iodothyronine (T4)]
Tri-iodothyronine (T3)Tri-iodothyronine (T3) Increase of Increase of oxidation of sugars oxidation of sugars by most body by most body cells; induction of cells; induction of some enzymessome enzymes
Thyroid Thyroid HormonHormoneses
HOHO
Response
Protein mRNA
Pre-mRNA
PPR
F F FR
PB
Regulation of Regulation of transcription transcription by thyroid hormones. by thyroid hormones. TT33 and and TT44 are tri-iodotyronine and tyroxine, are tri-iodotyronine and tyroxine, respectively.respectively.
TT33
TT44
TT33
TT44
TT33
TT33
TT33
Steroid HormonesSteroid Hormones Produced in the Produced in the adrenals, ovaries, testes, and adrenals, ovaries, testes, and
placentaplacenta.. Derived from Derived from cholesterolcholesterol.. EnzymesEnzymes in the various glands control the final in the various glands control the final
product. For example, cytochrome P450c11 which product. For example, cytochrome P450c11 which is located in the adrencortical cells, is involved in is located in the adrencortical cells, is involved in coritsolcoritsol production. This enzyme is lacking in the production. This enzyme is lacking in the gonads, that do not produce cortisol or gonads, that do not produce cortisol or aldosterone.aldosterone.
Gonads, however, can produce Gonads, however, can produce dihydroxytestosterone, estradiol, or dihydroxytestosterone, estradiol, or progesteroneprogesterone depending upon the enzymes depending upon the enzymes present in the gonadal tissue.present in the gonadal tissue.
Over Over 50 50 different steroid metabolites have been different steroid metabolites have been described.described.
Cholesterol Metabolism
Steroid Hormones
S SS S
SSS
S
S
S S
SPB
HSPHSP
HSPHSP
R
R R R RHSPHSP
HSPHSP
R
F R R PP
Response
Protein mRNA
pre-mRNA
F
Regulation of transcription by steroid Regulation of transcription by steroid hormoneshormones
CatecholaminesCatecholamines Are synthesized in Are synthesized in nervous tissuesnervous tissues from which from which
the adrenal medulla is derived.the adrenal medulla is derived. Adrenal medullaAdrenal medulla is the major source for is the major source for
circulating circulating epinephrineepinephrine.. Synthesized from Synthesized from tyrosinetyrosine which is converted to which is converted to
dihydroxyphenylalanine (dihydroxyphenylalanine (DOPADOPA) by tyrosine ) by tyrosine hydroxylases.hydroxylases.
Subsequent conversions to Subsequent conversions to dopaminedopamine and then and then to nor epinephrine which is released by most to nor epinephrine which is released by most catecholamine-producing cells of the body.catecholamine-producing cells of the body.
In the adrenal medulla and a few other tissue, nor In the adrenal medulla and a few other tissue, nor epinephrine is converted to epinephrine is converted to epinephrineepinephrine..
The half life is The half life is 1-2 minutes1-2 minutes..Flight, fright, or fight!Flight, fright, or fight!
Prostaglandins and Prostaglandins and LeukotrienesLeukotrienes
They can be produced by most cells depending upon They can be produced by most cells depending upon lipid and enzyme content of the cells.lipid and enzyme content of the cells.
Arachidonic acidArachidonic acid, which is derived from lipid , which is derived from lipid metabolism, is the precursor compound.metabolism, is the precursor compound.
Depending upon the Depending upon the lipoxygenaselipoxygenase present in the present in the cell, either, HETE, prostaglandin (G2) cell, either, HETE, prostaglandin (G2) or leukotrienesor leukotrienes
CyclooxygenaseCyclooxygenase (involved in PGG(involved in PGG2 2 synthesis) is synthesis) is widely distributed throughout the body and is widely distributed throughout the body and is inhibited by aspirin, indomethacin, and other inhibited by aspirin, indomethacin, and other nonsteroidal and anti-inflammatory agents. nonsteroidal and anti-inflammatory agents.
The half-life is a few The half-life is a few secondsseconds..Several COX inhibitors!! - ProblemsSeveral COX inhibitors!! - Problems
Hormone AntagonistsHormone Antagonists
Examples of hormone antagonists used in Examples of hormone antagonists used in therapytherapyAntagonist toAntagonist to UseUseGrowth Hormone Acromegaly, DiabetesGrowth Hormone Acromegaly, DiabetesProgesteroneProgesterone Contraceptive, abortionContraceptive, abortionGlucocorticoidGlucocorticoid Spontaneous Cushing’s Spontaneous Cushing’s
SyndromeSyndromeMineralo-corticoid Primary and secondary Mineralo-corticoid Primary and secondary
mineralocorticoid excessmineralocorticoid excess
AndrogenAndrogen Prostate cancer Prostate cancerEstrogenEstrogen Breast cancerBreast cancerGnRHGnRH Prostate cancer Prostate cancer -Adrenrgic-Adrenrgic Hypertension, Hypertension,
hyperthyroidismhyperthyroidismProstaglandinProstaglandin Acute and chronic Acute and chronic
inflammatory inflammatory disease disease
TamoxifinTamoxifin
Hormone Hormone ReceptorsReceptors
andand
Signal Signal TransductionTransduction
Hormone Hormone ReceptorsReceptors
Cell surface Cell surface membranemembrane receptorsreceptors
Polypeptide hormones and catecholamines
CytoplasmicCytoplasmic receptorsreceptorsMost steroid and thyroid hormones
NuclearNuclear receptors receptorsestrogens
Secondary Messengeror Secondary Signal
CellularTrafficking
Enzymes
Activated Inhibited
Nucleus DNA SynthesisRNA Synthesis
ProteinSynthesis
MembraneEffects
Receptor
Effector
PlasmaMembrane
Hormone
A general model for the action of peptide hormones, catecholamines, A general model for the action of peptide hormones, catecholamines, and other membrane-active hormones. The hormone in the extra and other membrane-active hormones. The hormone in the extra cellular fluid cellular fluid bindsbinds to the receptor and to the receptor and activatesactivates associated associated effector(s)effector(s) systems, that may or may not be in the same molecule. systems, that may or may not be in the same molecule. This activation results in generation of an intracellular signal or This activation results in generation of an intracellular signal or second messengersecond messenger that, through a variety of common and branched that, through a variety of common and branched pathways, produces the final pathways, produces the final effectseffects of the hormone on metabolic of the hormone on metabolic enzyme activity, protein synthesis, or cellular growth and enzyme activity, protein synthesis, or cellular growth and differentiation.differentiation.
Receptors that span Receptors that span the membrane Seven the membrane Seven
timestimes
cAMPcAMPcAMP: synthesis and degradationcAMP: synthesis and degradation
cAMP
Amino acid Amino acid PhosphorylationPhosphorylation is is very important in intracellular very important in intracellular
signal transductionsignal transduction
S SerineProtein Kinases – transfer terminal Phosphate groups
from ATP to Serine, Threonine, or Tyrosine residues in proteins
Result in activation or inactivation of the recipient protein !
ATPATPATP
S Serine
Threonine
Y Tyrosine
Amino acidsthat can be
phosphorylated
Peptide hormone Peptide hormone receptorsreceptors
Huising, et.al.J. Endo. 2006. 189:1-25
General View of
Metabolism
Levels of blood sugar Levels of blood sugar (glucose)(glucose) regulate secretion regulate secretion
of hormones from of hormones from the pancreasthe pancreas
Pancreas secretes Pancreas secretes insulininsulin when glucose when glucose
levels are highlevels are high
InsulinInsulin binds to binds to insulin receptors insulin receptors on fat and muscle on fat and muscle and “promotes” and “promotes” glucose uptakeglucose uptake
Overall effect: blood Overall effect: blood glucoseglucose
levels return to normallevels return to normal
Glucose Tolerance Test
The Insulin ReceptorThe Insulin Receptor
Responsible for clearance of Responsible for clearance of glucoseglucose
In addition to binding insulin, it In addition to binding insulin, it possesses a tyrosine kinase possesses a tyrosine kinase activityactivity
It is involved in many cellular It is involved in many cellular activitiesactivities
Glucose Transporter Intracellular Trafficking
Insulin Receptor
Tyrosinekinase
Insulin-mediated glucose transport signaling pathwayInsulin
P IRS
PI3K
Akt P
IR
Glut4
Insulin-mediated glucose transport signaling pathway
Cell membrane
Xiao Chen, 2006Xiao Chen, 2006
Insulin
P IRS
PI3K
Akt P
IR
glucose
Insulin-mediated glucose transport signaling pathway
Cell membrane
Insulin-mediated glucose transport signaling pathway
Xiao Chen, 2006Xiao Chen, 2006
Time, Nov, 2006USA Life Expectancy; Low = 73.6; High = 80.0
Obesity is a Global Pandemic DiseaseObesity is a Global Pandemic Disease
USA TodayFeb. 9, 2010
USA TodayFeb. 9, 2010
Reduce
USA TodayFeb. 9, 2010
41 grams
Time, Nov, 2006USA Life Expectancy; Low = 73.6; High = 80.0
Insulin Signaling Pathways by C. Hooper http://www.abcam.com/index.html?Insulin Signaling Pathways by C. Hooper http://www.abcam.com/index.html?pageconfig=resource&rid=10602&pid=7pageconfig=resource&rid=10602&pid=7
Cartoon of Intracellular Signaling System Cartoon of Intracellular Signaling System Used By Many Peptide Hormones and Used By Many Peptide Hormones and
Growth FactorsGrowth Factors
For exampleFor example– InsulinInsulin– EGFEGF
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.
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.
Adapted from: Dr. Donald F. Slish, Biological Sciences Department,
Plattsburgh State University, Plattsburgh, NY.
Examples of therapeutics Examples of therapeutics developed based on these developed based on these types of receptors and the types of receptors and the associated tyrosine kinase associated tyrosine kinase
signaling systemsignaling system
Erbitux – ImcloneErbitux – Imclone Iressa - AstraZeneca Iressa - AstraZeneca
Gleevec – Novartis Gleevec – Novartis Herceptin - GenentechHerceptin - Genentech
EGF Receptor Signal Transduction Pathway SIGMA-ALDRICH
Tyrosine kinaseTyrosine kinase
Cell ProliferationCell Proliferation
Epidermal Growth Factor ReceptorEpidermal Growth Factor Receptor
EGF
ReceptorReceptor
DimerizationDimerization
Cell Cell MembraneMembrane
Cysteine Cysteine RichRich
DomainDomain
Tyrosine KinaseDomain
EGF
Signal Transduction
P P
******
******
EGFR FamilyEGFR 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 cancerNon-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 with the epidermal growth factor receptor (EGFR-TK).
• EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib.
Gefitinib is an anilinoquinazoline with the
chemical name 4-Quinazolinamine, N-(3-
chloro-4- fluorophenyl) -7-methoxy-6- [3-4-
morpholin) propoxy]
C22H24ClFN4O3
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
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 myeloid leukemia. In colony formation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows inhibition of Bcr-Abl positive colonies from CML patients. In vivo, it inhibits tumor growth of Bcr-Abl transfected murine myeloid cells as well as Bcr-Abl positive leukemia lines derived from CML patients in blast crisis.
In vitro studies demonstrate imatinib is not entirely selective; it also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF mediated cellular events
Gleevec (Novarits)
Monoclonal Antibody TherapyMonoclonal Antibody Therapy
Antibody to EGF R binds and blocks EGF from Antibody to EGF R binds and blocks EGF from bindingbinding
Cell Cell MembraneMembrane
Tyrosine KinaseDomain
EGF
Erbitux, ImcloneErbitux, Imclone
Therefore, no tyrosine kinase Therefore, no tyrosine kinase activity andactivity and
no intracellular signalingno 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 HER 2 = Human Epidermal Growth Factor Receptor 2Factor Receptor 2
Herceptin, Herceptin, a monoclonal antibody, a monoclonal antibody,
binds to HER2binds to HER2and ultimately results and ultimately results
in destruction of the cell in destruction of the cell
So two targets to inhibit EGF/EGFR So two targets to inhibit EGF/EGFR signalingsignalingEGF
ReceptorReceptor
DimerizationDimerization
Cell Cell MembraneMembrane
Tyrosine KinaseDomain
EGF
Signal Transduction
P P
11
22Colored slide: D-88Colored 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.Diabetes, con’t. Type IType I or or Insulin Dependent Insulin Dependent
Diabetes MellitusDiabetes Mellitus (IDDM)(IDDM) – Also called – Also called juvenilejuvenile diabetes - diabetes - lack of insulinlack of insulin
Type IIType II or or Non Insulin Dependent Non Insulin Dependent Diabetes MellitusDiabetes Mellitus (NIDDM)(NIDDM) – Also – Also called called adultadult onset diabetes - onset diabetes - insulin insulin present but cells do not respond present but cells do not respond that is they are“insulin resistant”.that is they are“insulin resistant”.
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.
Facts: (Diabetes 1996 Vital Statistics, ADA)
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.
Diabetes, con’t.Diabetes, con’t.
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.
Types of diabetes mellitus(Diabetes 1996 Vital Statistics, ADA)
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.
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.
Types of diabetes, con’t.Types of diabetes, con’t.
