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Year 3 - Biotechnology > 7 - Hematopoietic Growth Factors > Flashcards

7 - Hematopoietic Growth Factors Flashcards

1
Q

What is hematopoiesis?

A

Process of production and maturation of blood cells

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2
Q

How does the stem cell pool maintain itself?

A
  • By asymmetrical cell division w/o extensive depletion
    • When a stem cell divides, one daughter cell remains in the stem cell pool and the other becomes a committed colony-forming unit (CFU)
    • CFUs proliferate at a greater rate than the other stem cells and are more limited in self-renewal than pluripotent hematopoietic stem cells
    • Stem cell splits into 2 cells, then one cell will continue to divide but the other won’t
  • When a multipotential hematopoietic stem cell is stimulated by colony stimulating factor (CSF), it splits into either common myeloid progenitor or common lymphoid progenitor
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3
Q

Cells committed to myeloid pathway can develop into ___

A

RBCs (erythrocytes), platelets (thrombocytes), monocytes and macrophage, granulocytes (neutrophils, eosinophils and basophils), or tissue mast cells

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4
Q

Cells committed to lymphoid pathway give rise to ____

A

B- or T-lymphocytes (natural killer cells) or plasma cells

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5
Q

What is the difference between white cell factors, red cell factors, and platelet factors?

A
  • White cell factors = granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (Gm-CSF)
  • Red cell factors = erythropoietins (EPO) and darbepoetin alfa
  • Platelet factor = thrombopoietin (TPO) / megakaryocyte growth and development factor (MGDF) and interleukin-11 (IL-11)
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6
Q

What is an early acting HGF?

A

Stem cell factor

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7
Q

Pharmacology and physiology of HGFs

A
  • HGFs bind to their specific cellular membrane receptors => cascade of intracellular signaling and altered gene expression
  • May induce another gene expression that produces a different HGF or cytokine, which in turn to stimulate another target cell
  • Therefore, it is difficult to delineate the pharmacologic activity of individual HGF
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8
Q

Cytokine receptor families

A
  • Growth hormone family = cytokines that signal through a single chain (EPO, G-CSF)
  • gp130 family = cytokines that signal through gp130 or a gp130-related subunit
  • gp140 family = cytokines that signal through the gp140-subunit and a ligand-binding-subunit (GM-CSF)
  • Interleukin-2 receptor family = cytokines that signal through a common gamma-chain and alpha and/or beta ligand-binding subunits
  • Interferon family = cytokines that signal through 2 or more subunits
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9
Q

Signaling pathway of cytokines

A
  • Ligand binding to cytokine receptors induces their dimerization, which then phosphorylates JAKs
  • Phosphorylated JAKs subsequently phosphorylate STATs
  • Activated STATs dimerize, translocate to the nucleus whereby they activate or repress target gene promoters
  • In addition to JAKs and STATs, cytokine receptors also activate additional signaling pathways involving proteins such as Akt and extracellular responsive kinase (ERK)
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10
Q

In vitro activity of HGFs

A
  • Determined by evaluating the effect of adding HGF to cell culture containing immature progenitor cells from the bone marrow
  • Lineage specific growth factor (G-CSF, EPO) predominantly affect one cell lineage
  • Multilineage growth factor (GM-CSF) affect more than one cell lineage
  • This phenomenon is concentration dependent (ex: GM-CSF regulate monocytes and granulocytes at 5-20 pg/mL while they regulate eosinophils and platelets at 20-2000 pg/mL)
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11
Q

In vivo activity of HGFs

A
  • Can be evaluated by measuring endogenous concentrations under different conditions or by administering growth factors to animals or humans
  • Results are often consistent w/ those predicted by in vitro studies
  • Differences between the in vivo and in vitro activities of HGFs could be due to interspecies variability, difference in clearance, PK, and glycosylation
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12
Q

Cellular source of G-CSF

A

Monocytes, fibroblasts, endothelial cells, bone marrow stroma

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13
Q

Cellular source of GM-CSF

A

T-cells, monocytes, fibroblasts, endothelial cells

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14
Q

Cellular source of EPO

A

Kidney, liver

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15
Q

Cellular source of SCF

A

Fibroblasts, bone marrow stroma

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16
Q

Cellular source of TPO

A

Kidney, liver

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17
Q

Stimuli for release of G-CSF

A

Lipopolysaccharide induction, TNF-alpha, IL-1, cytokine activation

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18
Q

Stimuli for release of GM-CSF

A

Antigens, lectins, IL-1, lipopolysaccharide induction, TNF-alpha

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19
Q

Stimuli for release of EPO

A

Hypoxia

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20
Q

Stimuli for release of SCF

A

Constitutively expressed

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21
Q

Stimuli for release of TPO

A

Constitutively expressed

22
Q

Physiological role of G-CSF and GM-CSF. Compare and contrast functions of each.

A
  • 2 myeloid growth factors have complementary role
  • G-CSF helps maintain neutrophil production during steady-state conditions and increase production during infection
  • GM-CSF is a locally active growth factor that remains at the site of infection to localize and activate neutrophils
  • rhG-CSF reduces neutrophil maturation time from 5 days to 1 day, leading to rapid release of mature neutrophils from the bone marrow into circulation, while rhGM-CSF doesn’t reduce the mean maturation time
  • Neutrophils treated w/ rhG-CSF show normal intravascular t1/2 while neutrophils treated w/ rhGM-CSF have increased serum t1/2 of 48 h
  • Neutrophils treated w/ rhG-CSG have enhanced superoxide production in response to chemoattractant; rhGM-CSF also enhances superoxide production but requires a long incubation
23
Q

Physiological role of EPO

A
  • Increases RBC count by causing committed erythroid progenitor cells to proliferate and differentiate into normoblasts (a nucleated precursor cell in the erythropoietic lineage)
  • Shifts reticulocytes (mature RBCs) from the bone marrow into peripheral circulation
  • Unlike other HGFs, EPO release isn’t mediated by inflammatory stimuli
    • Tissue hypoxia resulting from anemia induces kidney to increase EPO production
24
Q

Physiological role of SCF (stem cell factor)

A
  • SCF = early acting HGF that stimulates proliferation of primitive hematopoietic and non-hematopoietic cells
    • Produced by bone marrow stroma and has important role in steady-state hematopoiesis
  • Circulates in relatively high concentrations in normal human plasma
  • In vitro, SCF alone has minimal colony stimulating activity on hematopoietic progenitor cells, however, it synergistically increases colony-forming or stimulatory activity of other HGFs
25
Q

Target cells of G-CSF

A

Granulocyte progenitors, mature neutrophils

26
Q

Target cells of GM-CSF

A

Granulocyte, macrophage progenitors, eosinophil progenitors

27
Q

Target cells of EPO

A

Erythroid progenitors

28
Q

Target cells of SCF

A

Granulocyte-erythroid progenitors, lymphoid progenitors, NK cells

29
Q

Target cells of TPO

A

Stem cells, megakaryocytes, erythroid progenitors

30
Q

Target cells of IL-11

A

Early hematopoietic progenitors, megakaryocytes

31
Q

Actions of G-CSF

A

Increase neutrophil counts

32
Q

Actions of GM-CSF

A

Increase neutrophil, eosinophil, and monocyte counts

33
Q

Actions of EPO

A

Increase RBC counts

34
Q

Actions of SCF

A

Increase pluripotent stem cells and progenitor cells for all other cell types

35
Q

Actions of TPO

A

Increase platelet counts

36
Q

Actions of IL-11

A

Increase platelet counts

37
Q

Pharmaceutical issues w/ HGFs

A
  • Pharmaceutical formulation **know that filgrastim can’t be diluted w/ saline (will form precipitate) and must use 5% dextrose
  • Storage and stability
    • All recombinant HGF preparations should be kept from freezing and shouldn’t be shaken as shaking can denature the proteins
    • All preparations should be visually inspected for participate matter before administration
  • rhG-CSF = filgrastim, lenograstim, and pegfilgrastim (end in “grastim”)
  • rhGM-CSF = molgramostim and sargramostim (end in “gramostim”)
38
Q

Clinical use of HGFs

A
  • Ability to augment hematopoietic cell cycling using hematopoietic growth factors has led to 2 interrelated areas of clinical investigation
    • Application of hematopoietic growth factors to facilitate more dose-intense tx (in an attempt to improve upon primary therapeutic outcomes)
    • Application for supportive care management (in an attempt to decrease tx-related complications)
  • Established uses –> cancer tx (chemotherapy-induced neutropenia, bone marrow or stem cell transplantation, anemia), peripheral blood progenitor cell mobilization for harvesting and transplantation, severe chronic neutropenia, thrombocytopenia
39
Q

Describe the use of HGFs for prophylaxis in the context of chemotherapy

A
  • Prophylactic use: administration of a growth factor to prevent febrile neutropenia
    • Primary prophylaxis: use of CSFs following the first cycle of multicourse chemotherapy prior to any occurrence of febrile neutropenia
    • Secondary prophylaxis: use of CSFs to prevent a subsequent episode of febrile neutropenia in a pt who has already experienced infectious complications in a previous chemotherapy cycle
40
Q

Describe the therapeutic use of HGFs in the context of chemotherapy

A
  • Therapeutic use: administration of a growth factor at the time when neutropenia or neutropenic fever is documented in a pt who had not been previously receiving CSFs (colony stimulating factors)
  • CSF use can permit chemotherapy dose maintenance or allow modest increases in dose intensity in clinical scenarios where the main toxicity is neutropenia
    • Ex: delivery of dose-dense chemotherapy q2weeks w/ G-CSF support has improved survival compared w/ standard q3week dosing in women w/ breast cancer receiving adjuvant cyclophosphamide and doxorubicin, followed by paclitaxel
41
Q

What is a reason NOT to prescribe CSF support?

A

No indications for CSF use to treat uncomplicated neutropenia w/o fever; thus, low neutrophil counts alone don’t represent a reason to prescribe CSF support

42
Q

Recommendations for CSF use in the context of chemotherapy

A
  • Effective way to use CSFs is 24-48 h after chemotherapy is completed; CSF therapy should be continued until neutrophil recovery is adequate
    • Check blood counts before initiating the next cycle of chemotherapy
  • Initiation of the next cycle of chemotherapy is not recommended for at least 24 h after the completion of CSF therapy b/c of potential concern that progenitor cells, which are rapidly dividing following CSF administration, may be sensitized to chemotherapy
  • B/c of the same concern, concurrent administration of CSFs w/ chemotherapy or radiotherapy isn’t recommended outside clinical trials
43
Q

Dose-intensity – hematopoietic cell transplantation

A
  • Autologous stem-cell and/or BMT – high dose chemotherapy w/ autologous hematopoietic stem-cell support has been used in the tx of several malignancies
  • Prolonged period of high-dose therapy shows myelosuppression w/ increased risk of infectious and bleeding complications
  • Several randomized trials have documented that CSFs can effectively reduce duration of neutropenia, infectious complications, and hospitalization in px who are receiving high-dose chemotherapy w/ autologous BMT
  • Allogenic BMT: similar beneficial effects of CSFs have been seen following allogeneic BMT, and the routine use of hematopoietic growth factors is appropriate in this setting
    • There has been no evidence of any increase in graft vs. host disease, graft rejection, or relapse w/ the use of CSFs
44
Q

HGF use for supportive care of anemia

A
  • Anemia can be caused by chronic renal failure in predialysis or dialysis px, or zidovudine tx in HIV px, or chemotherapy in cancer px
  • EPO can be used to treat anemia in the above conditions as well as px w/ anemia, who schedule for elective, non-cardiac, non-vascular surgery
  • Anemia caused by chemotherapy is due mainly to drug effects on bone marrow precursor cells and is proportional to chemotherapy dose intensity
  • In addition, w/ platinum agents, anemia may be related to renal effects of these drugs on the production of EPO
45
Q

Concerns w/ HGFs

A
  • Many HGFs, especially multipotential factors that act on early progenitor cells, are associated w/ constitutional sx -> bone pain, fever/ chills, rash, myalgia, injection-site reaction (pain), edema
  • Potential for generating immunogenic reactions
  • Short plasma t1/2 necessitating repeated parenteral administration
46
Q

Types of immune responses to HGFs

A
  1. Activation of the classical immune system by foreign proteins, similar to the immune response against pathogens or vaccines
  2. Breach of B and T cell tolerance to autologous proteins – a complicated series of immunological events that isn’t fully understood
47
Q

Epoetin-associated pure red cell aplasia

A
  • PRCA is characterized by severe anemia, low reticulocyte count, erythroblasts absence, epoetin non-response, and neutralizing antibodies against EPO
  • *When you give a pt a protein drug, must think that they can develop Abs (less severe) or it might cause breach of immune tolerance (more severe)
48
Q

What are the 5 amino acid substitutions in darbepoetin?

A
  • Ala30Asn
  • His32Thr
  • Pro87Val
  • Trp88Asn
  • Pro90Thr
49
Q

Compare and contrast epoetin and darbepoetin

A
  • Epoetin has the same AA sequence as erythropoietin while darbepoetin has 5 AA substitutions
  • Epoetin has 3 N-linked glycosylation sites while darbepoietin has 5 N-linked glycosylation sites
  • Epoetin has higher receptor binding; darbepoetin has longer serum t1/2 and biological activity
50
Q

Physiological role of TPO (thrombopoietin)

A
  • TPO/MGDF stimulates production of megakaryocyte precursors, megakaryocytes and platelets
  • Endogenous TPO is produced by the liver and enters the peripheral circulation
    • Eventually reaches bone marrow and stimulates bone marrow megakaryocytes to produce platelets
  • IL-11 works synergistically w/ IL-3, TPO, MGDF or SCF to stimulate various stage of megakaryocytopoiesis and thrombopoiesis

Year 3 - Biotechnology (11 decks)

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