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64 Cards in this Set

  • Front
  • Back
What is emphysema (3)
1)alteration of lung architecture
2)destruction of bronchioles and wall of alveoli
3)results in abnormally enlarged airspaces
Genetic mutation that causes familial emphysema
342 Glutamic acid(E) to a lysine(k) in alpha1-antiprotease
How to treat familial emphysema
give alpha1-antiprotease from blood or recombinant
How is Alpha1-PI inactivated
it has a Met in the AS that can be turned into MET sulfoxide to inactivate it
Smoking effect on lungs (3)
1)large number of macrophages to lungs after bronchial lavage
2)smoke causes the macrophages release a chemotactic to attract neutrophils to the lungs
3)smoke stimulates release of elastase from macrophages and neutrophils in the lungs
Levels of alpha1-PI in familial emphysema pts
less than 15% of normal
Gene therapy for familial emphysema (4)
1)part of liver removed
2)converted into single cells and cultured in vitro
3)retrovirus construct w/ corrected gene is introduced into cells under ex vivo conditions
4)modified cells are reintroduced
Categories of gene involved w/ cancer (3)
2)tumor suppressor genes
3)DNA repair genes
When tumor suppressor genes are unregulated....(2) (and 3ex)
1)cell divides when it should NOT
2)inhibitor signals fail to reach nucleus

ex)p53, BRCA1, APC
When Oncogenes are unregulated... (and 4ex)
1)cell divides in absence of stimulation by external growth factors

ex)ras, myc, jun, PDGF
Gene therapy strategies (4)
1)replacement and knockout gene therapy
2)suicide gene therapy
3)immunomodulatory gene therapy (modify cell to trigger immune response)
Gene transfer methods (broad categories) (2)
Replacement gene therapy for cancer (4)
1)replacing mutated/missing (usually a tumor suppressor gene) gene w/ normal copy that keeps cell growth and division under control
2)can involve induction of apoptosis
3)production of changes in cell growth, behavior, invasiveness or metastatic ability
4)gene should exhibit GENETIC DOMINANCE (only need 1 normal copy of gene to restore fxn)
Replacement gene therapy for cancer limitations (3)
1)large # of target genes known to induce or maintain malignancy (cancer usually not due to just 1 mutation)
2)difficulty of transducing in enough cancer cells to result in a cure
3)BYSTANDER effect
Bystander effect
death of more cells than are actually transduced
Knockout gene therapy for cancer approaches (3)
1)deliver DOMINANT mutant oncogene to negate effect of cancer causing oncogene
2)inhibit translation of oncogene by inserting DNA that codes for RNA/ribozyme that will destroy the oncogene's RNA
3)reduce levels of oncogene product that are being made in cell via antisense mRNA or siRNA
Suicide Gene therapy
a)transduction of a gene that transforms a nontoxic form of a drug (prodrug) into a toxic substance
Suicide therapy ex (2)
1)5-FC to 5-FU via cytosine deaminase (the transduced gene)
2)acyclovir to phosphorylated analog leading to cell death (via thymidine kinase, the transduced gene)
Immunomodulatory gene therapy
a)works via...(2)
b)approaches used...
a1)induction of cellular immune responses to metastatic lesions
a2)cytokine gene is introduced to tumor cell to stimulate a systemic immune response against tumor-specific antigens; vaccinating the pt

b)in vivo and in vitro
Immunomodulatory ex vivo approach (3)
1)modify tumor cells ex vivo w/ a cytokine gene
2)put modified cells back into pt after cell has been irradiated to prevent further cell division
3)letting immune system create a systemic antitumor response
Transduction def
intro of new genetic material into a cell using a viral vector
Transfection def.
intro of free genetic material typcially by chemical manipulation of cells
Non-viral vectors
use chemical or mechanical manipulation to intro genes into cells (used in vitro usually)
4 Non-viral transfer methods
1)in vitro microinjexn of DNA coated onto gold & using a GENE GUN to inject DNA into tissue
2)artificial membrans (liposomes) that fuse w/ cellular membranes and carry transgenes
3)complexes of DNA attached to small protein (ligands) that can bind to receptors on cancer cells and then bring DNA into the cell
4)creation of pores in cell memb. by electrical pulse to get foreign DNA into cell (electroporation)
Retrovirus vector w/ co-transfection has...
therapy gene and packaging sequence so virus only carries these 2 genes
Retrovirus advantages (2)
1)can intro a therapeutic gene where it will become stably integrated and expressed
2)can enter any cell making them very useful in vitro
Retrovirus disadvantages (3)
1)not very selective; limiting their use for direct admin into a person
2)can only infect/integrate into actively dividing cells
3)could put gene in a location promoting new oncogenesis
Adenovirus desc. (5)
1)DNA viruses
2)larger more complex than retrovirus
3)50 disctinct adenoviruses
4)include many common cold viruses
5)transgenes inserted where 2 viral genes that are critical for viral replication naturally exist
Advenovirus vectors adv. (5)
1)can put genes in dividing and NONdividing cells
2)can deliver siRNA and other antisense agents
3)high efficieny of infexn into human cell types b/c binds to surface receptor most common on human cells
4)infexns are generally stable over time
5)can package larger DNA molecules than retroviruses
Advenovirus vectors limitations (3)
1)can cause immune response in host
2)host can develop neutralizing Ig's
3)non-integrative vector that limits express of transgene to a few cell divisions
Adenovirus as tumor specific killers (4)
1)use the virus as a virus; killing a host cell
2)immunomodulatory strategies
3)transductional/transcriptional targeting
4)siRNA targeting
Virotherapy w/ transDUCTional targeting (w/ adenovirus) mechanism (3)
1)virus recognizes receptor made only by tumor cells
2)virus takes over cancer cells and makes copies til cell is dead
3)cell bursts and virus infects and kills other cancer cells
Virotherapy w/ transCRIPional targeting (w/ adenovirus) mechanism (2)
1)virus will infect normal and cancer cells
2)BUT will only replicate in tumor cells b/c it has a promoter that can only be turned on in tumor cells
Adeno-associated virus vectors def.
adeno-associated virus is a parovirus w/ a single stranded DNA genome of 5000bp
Adeno-associated virus vectors adv. (3)
1)small size makes them easy to manipulate genetically
2)integrate stably into a host genome
3)capable of infecting nondividing cells
Adeno-associated virus vectors disadv
1)small genome size limits amt of transgenic DNA that can be introduced into it
Herpes simplex virus vector def.
very infexous to epithelial cells; as well as nerve tissue ther natural target
Herpes simplex virus vector adv (3)
1)accomadate large amounts of transgenic DNA
2)high efficiency of entering a wide range of cells
3)remain dormant in cells w/o replicating, allowing for long-term expression of transgenes
Herpes simplex virus vector disadv (3)
1)toxic to cells in their replicative (more SEs)
2)induce immune reponse
3)potential problems for neuronal cells they enter
Other viral vectors (3)
1)epstein-barr virus
2)polio virus
3)engineered bacteriophages
AA's consists of... (5)
1)alpha carbon
4)R group
5)asymetic carbon center (EXCEPT GLYCINE)
Ionization state of AA is...
pH dependent
Protein drugs differ from traditional drugs via...
can retain 100% of chemical composition of active protein, yet be biologically inactive (via conformation differences)
Never ____ protein solutions
peptide begins @ ___ and ends @ ____
begins at free amino
ends at free COOH
Protein degradation pathways (2)
Chemical instability of proteins via... (3)
1)covalent modification of protein via bond formation or clevage
2)results in generation of a new chemical entity
3)occurs thru some chemical rxn such as hydrolysis, deamidation, oxidation, racemization
Hydrolysis def in relation to AAs
cleavage of the "amide" or peptide bond
____ has ASPARTATE-PROLINE hot-spots promoting hydrolysis
human recombinant IL-11
Deamidation happens to what peptides
peptides containing AAs such as Gln or Asn undergo hydrolytic deamidation to produce a free carboxylic acid
Deamidation of a peptide results in.... (2)
1)conversion of a natural residue to an acidic residue
2)can alter biological activity and protein fxn
Major pathway of protein degradation (in solution and lyophilized)
Oxidation desc.
occurs in presence of oxygen and is influenced by temp and metal ions (so store in plastic)
____ residues are especially prone to oxidation
How to protect proteins from oxidation
Pack under nitrogen/argon/inert gas
Racemization process (3)
1)conversion of L-AAs to D,L-mixtures
2)occurs thru a carbanion intermediate
3)may create peptide bonds susceptible to proteolytic enzymes and alter biological activity
Physical Instability
b)4 main classes
a)no change in chemical composition yet results in an inactive or low activity product
b)denaturation, surface adsorption, aggregation, precipitation
a)factors affecting it
b)can be...
c)denatured protein is generally...
a)temp, pH, organic solvents/salts
b)reversible or irreversible
c)less soluble than native protein
Surface adsorption (3)
1)molecule prefers to localize @ the interface (solid-liquid/air-liquid)
2)leads to denatuation
3)larger proteins are more prone to it
proteins adhere to the wall of the containers, also referred to as frosting
Desorption may lead to...
aggregation and precipitation since hydrophobic inner core of protein is exposed @ aqueous phase
Aggregation (3)
1)occurs when hydrophobic regions of denatured protein interact w/ each other forming aggregates
2)minimized by maintaining protein in its native stable conformation
3)aggregated proteins generally lose biological fxn
Precipitation (2)
1)macroscopic equivalent of aggregation
2)usually occurs in conjxn w/ denaturation