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_______ is a recombinant enzyme (carboxypeptidase G2, CPDG2) which lowers bl levels of methotrexate, reducing its concentration to below the threshold for serious toxicity.

Voraxaze

Glucarpidase

Voraxaze

________ converts methotrexate to its inactive metabolites DAMPA and glutamate.

Voraxaze

DAMPA and glutamate are metabolized by the _______, providing an alternative route of methotrexate eliminate to renal clearance during high-dose txm.`

liver

________ is specifically indicated for the txm of toxic plasma methotrexate concentrations (>1 micromole/L) in pts w/ delayed methotrexate clearance due to impaired renal function.

Voraxaze

What is the route of administration for Voraxaze (glucarpidase)? What is the recommended dose?

Single IV injection of 50 units/kg as bolus injection over 5 mins.

It takes _____ years on average for an experimental drug to travel from the lab to U.S. pts.

10-15

Only __ in 5,000 compounds that enter pre-clinical testing make it to human testing. __ of these is approved.

5;1

On average, it costs a company _________ to get one new med from the lab to U.S. patients.

$1.3 billion

Takes 6.5 years; lab and animal studies; assess safety, biological activity, and formulations, 5,000 compounds evaluated

Discovery/pre-clinical testing

Takes 1.5 years; 20-100 healthy volunteers; determine safety and dosage

Phase I

Takes 2 years; 100-500 patient volunteers; evaluate effectiveness, look for side effects

Phase II

Takes 3.5 years; 1,000-5,000 patient volunteers; confirm effectiveness, monitor adverse reactions from long-term use

Phase III

Additional post-marketing testing required by FDA

Phase IV

Proteins (catalysts) which speed up reactions utilized specific substrates (endogenous).

Enzymes

Recombinant tissue plasminogen activator; clot buster for acute MI (enzyme)

Reteplase

There are over __ mAbs approved for human use.

30

________ are produced from cell culture (biotech); exert effect on cell surface receptors or scavenge proteins in the ECM; rarely enter cells; very specific in action

Monoclonal Antibodies

Glycoprotieins that are soluble mediators in cell communication, represented by large groups (>100) of IL and IFNs; produced during effector phases of immune response or host defense

Cytokines

Cytokines exert their regulatory effects on specific organs/tissues _________ the site of excretion. aka ___________

nearby; paracrine

__________ is a recombinant granulocyte colony-stimulating factor

Neupogen (Filgrastim)

Filgrastim

Neupogen

_______ is a GF used to enhance neutrophil proliferation and is indicated for CA patients receiving myelosuppressive chemo or BM transplant; pts w/ myeloid leukemia; pts w/ severe neutropenia

Neupogen (Filgrastim)

Most endogenous GFs are ________ that stimulate production of certain cell types.

glycoproteins

A ________ is a substance produced by endocrine glands, released in very low concentrations into the bl stream.

hormone

A hormone exerts regulatory effects on specific organs/tissues _______ the site of site of secretion. aka ________

distant from; endocrine

Some hormones are not proteins, like ________.

Steroids

__________ are synthetic molecules that bind to specific intracellular mRNA. They are made of about 13-25 nucleotides that are complementary to mRNA in a region of a coding sequence designed as a sense strand. By binding to mRNA, these stop translation.

Antisense oligonucleotides

__________ is used for the txm of CMV retinitis in persons w/ AIDS.

Vitravene (fomivirsen)

fomivirsen

Vitravene

Vitravene

fomivirsen

Vitravene is a(n) ______________.

antisense oligonucleotide (AS-ON)

__________ are RNA/DNA molecules that recognize specific proteins. They fold into a 3D structure and bind to proteins.

Aptamers

______ is an anti-VEGF inhibitor approved by the FDA for the txm of wet age-related macular degeneration (injected into eye)

Mucagen (pegaptanib Na injection)

pegaptanib sodium injection

Mucagen

Biologic drugs are homogeneous or heterogeneous mixtures?

heterogeneous

Biologics have a logP of > or < 0.5?

logP < 0.5

LogP of > 0.5 means high or moderate-low solubility

Moderate-low

Log P of < 0.5 means high or moderate-low solubility?

high

Biologics are distributed to any organ/tissue or are limited to plasma/extracellular fluid?

Limited to plasma/extracellular fluid

Are biologics routinely metabolized or catabolized to aa (peptides)?

catabolized to aa (peptides)

___________ is the movement of drug from the site of application into blood stream or target tissue.

Absorption

___________ is the effect of drug on non-target tissues or cells.

Toxicity

___________ is the transformation, detoxification, conjugation, or bioactivation (prodrugs) of drugs

Metabolism

___________ is the movement of drug from blood to target site of action; greatly affected by plasma protein binding

Distribution

Voraxaze converts methotrexate to its inactive metabolites ________ and ________.

DAMPA; glutamate

________ implies drug is administered by injection or infusion

Parenteral

For biologics, preferred routes of administration include _________ & ________.

parenteral; subcutaneous

What's a biologic (protein) that is administered by inhalation?

Exubera (inhaled insulin powder

_____ and _____ are examples of enzymes that don't end in '-ase' and catalyze the cleavage of peptides.

Trypsin; pepsin

The following are disadvantages of oral administration:

1) Drug-drug or drug-food interactions
2) First-pass effect (liver metab); can be advantageous for prodrugs
3) Liver enzyme induction
4) Digestive tract irritation

The following are disadvantages of parenteral administration:

1) High initial drug concentration
2) Invasive- risk of infection
3) Requires a certain skill level

The ratio of octanol solubility to water solubility is measured through LogP. A high log P is _______ and a low LogP is ________.

Lipid soluble; water soluble

H bond donors can occur between atoms of __, __, __, and a hydrogen.

N, O, F

Lapinski "Rule of Five (RO5)" must meet 3 out of 4 of the following criteria:
MW ______
# H bond acceptors ___
# H bond donors ___
___ < LogP < ___

< or equal to 500; < or equal to 10; < or equal to 5; -2 < LogP< 5

________ is a potent and selective leukotriene D4 receptor antagonist; indicated in adult and pediatric pts 2 y/o and older.

Singulair (montelukast Na)

_________ is used for the prophylaxis and chronic txm of asthma; the relief of daytime/nighttime s/s of seasonal/perennial allergic rhinits

Singulair (montelukast Na)

______ is a (IgG-1k) humanized mAb that blocks IgE-mediated mast cell degranulation

Xolair (omalizumab)

Omalizumab

Xolair

______ is indicated for adults and adolescents (12+) w/ moderate-severe persistent asthma who have a + skin test or in vitro reactivity to a perennial skin allergen and who s/s are inadequately controlled w/ inhaled corticosteroids.

Xolair (omalizumab)

Xolair (omalizumab) is administered ____________.

Subcutaneously

________ is an FDA-approved protein kinase inhibitor used in oncology.

Imatinib

_______ is another non '-ase' enzyme

Renin

Recently, patent expiration and loss of market exclusivity on several pharmaceuticals (biologics) stimulated a debate on the role of generic (____________) biologics.

Biosimilar; follow-on

___% of proteins are misfolded.

60

DNA = about ____ BP in humans and contains about _____ genes.

3 x 10^9; 25,000

Nuclear DNA contains about ___ Mb and ____ genes.

3,300; 25,000

Mitochondrial DNA contains about ___ kb and ___ genes.

16.6; 37

Out of nuclear DNA, __% is genes and __% is extragenic DNA.

25; 75

________ DNA are composed of repeats (tandem, clustered, or interspersed).

Extragenic

Out of nuclear genes, __% is coding DNA and __% is non-coding DNA (introns, UTR, fragments)

10; 90

In mitochondrial DNA, __ are rRNA genes, __ are tRNA genes, and __ are polypeptide encoding genes.

2; 22; 13

In the nuclear genome, replication utilizes strand-coupled mechanisms that use DNA pol ___ and ___.

Alpha; delta

In the mitochondrial genome, replication utilizes strand-coupled and strand-displacement models; only uses DNA pol ___.

Gamma

Mitochondria can contain ___ 'plasmid-size' mitochondrial genomes.

2-3

A _________ is a very long, continuous piece of DNA, which contains genes, regulatory elements, and other intervening sequences; bundles w/ histones (major protein component of chromatin)

Chromosome

______ is a rare, progressive neurodegenerative disease caused by the decreased ability of cells to produce sufficient APT.

MELAS (mitochondrial encephalopathy lactic acidosis stroke-like episodes)

MELAS stands for....

Mitochondrial encephalopathy lactic acidsos stroke-like episodes

80% of those diagnosed w/ MELAS have a ________ mutation in dihydrouridine loop of tRNA.

3243 A --> G point

_________ explains the variation in severity of the disease among siblings.

Heteroplasmy

_________ is the presence of a mix of more than one type of an organelle genome (mtDNA) w/in a cell. It is frequent for mutations to affect only some copies of mtDNA, while the remaining ones are undaffected.

Heteroplasmy

Drugs most often used to treat MELAS include ________ and ________.

antioxidants and vitamins (like coenzyme Q10, L-arginine, B vitamins, Levocarnitine, etc.); no FDA-approved drugs yet.

The ribose has a -OH on the ___ C and deoxyribose does not.

2'

The pyrimidines are __, __, and __; the purines are __ and __.

Uracil, cytosine, and thymine; adenine and guanine

A __________ has a nitrogen base linked by a glycosidic bond of C1' of a sugar (ribose/deoxyribose)

Nucleoside

A nulceoside has a N base linked by a _________ to C1' of a sugar (deoxyribose/ribose)

glycosidic bond

Adenine and guanine become ________ and _______ when they are incorporated into nucleosides.

adenosine; guanosine

Cytosine and thymine become _______ and _______ when they are incorporated into nucleosides.

Cytidine; thymidine

Lamivudine, Brivudin, Valaciclovir, Valganciclovir, and Cidofovir are examples of ___________.

Nucleic acid analogs: antiviral drugs (shuts down replication)

Nucleotides are linked by ________ bonds.

phosphodiester

Order of bases always read from _____.

5' --> 3'

C and Gs are linked by __ H bonds; A and Ts are linked by __ H bonds.

3;2

Physical properties of DNA:
__ nm in width
__ bases/turn
__ nm/turn

2.0; 10; 3.4

__________ compounds bind to DNA helices, forming intrastrand crosslinks b/t adjacent guanines in a similar way to cisplatin.

Dinuclear azole-bridged platinum

DNA is in a relaxed form, but ___________ can occur when ccDNA is subject to structural strain.

supercoiling

Strain is a result of __________ in ccDNA (DNA has fewer helical turns than would be expected for the B-form)

underwinding

______ is a problem for both pro- and eukaryotic DNA

Strain

________ is an enzyme that helps to relieve torsional strain created by DNA replication.

Topoisomerase

______ catalyze addition of acetyl group to lysine side chain amino acid on proteins. (increase transcription)

HAT or histone acetyltransferase

______ catalyze the removal of acetyl groups (gene repression through chromatin condensation)

HDAC or histone deacetyltransferase

In human GI cancers, histone acetylation is globally reduced or increased?

reduced

________ cause the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells (program cancers to self-destruct!)

HDAC inhibitors

________ have been shown to act selectively on gene expression, and are inducers of cell growth, arrest, differentiation, and death (in vitro and in vivo)

HDAC inhibitors

HDAC inhibitors have been shown to act selectively on _____________ and are inducers of cell growth, arrest, differentiation, and death (in vivo and in vitro)

gene expression

________ and ________ are examples of FDA-approved HDAC inhibitors used in cutaneous T-cell lymphoma (a type of non-hodgkin's lymphoma)

Vorinostat (Zolinza) [orally-active] and Romidepsin (Istodax) [IV infusion cyclic peptide

HDAC inhibitors (increase/decrease) acetylation of histones, thereby (increasing/decreasing) transcription of genes that have been silenced.

increase; increasing

HDAC inhibitors promote growth arrest by inducing the expression of __________ or _________ genes and are commonly used as anticancer drugs.

tumor-suppressor or pro-apoptotic

___ is the temperature it takes to unwind DNA.

90 C

_______ catalyzes dsDNA separation at origin.

Helicase

_______ stabilize ssDNA that has been separated

DNA binding proteins

_______ catalyzes the addition of short RNA primers to template strand.

DNA primase

_______ catalyzes the addition of new nucleotides to form new strands.

DNA polymerase

_______ catalyzes removal of RNA primer and inserts the correct bases (DNA pol has this kind of activity)

Exonuclease

_______ catalyzes the joining of Okazaki fragments and seals the sugar-phosphate backbone.

Ligase

Initiation--the replication origin is at a consensus sequence of 245 bps in the genome that is rich in ___________.

GATC sequence repeats

___________ is the enzyme that stays in front of the replication fork; introduces a nick in the DNA backbone allowing the rotation of one strand around the other, relieving torsional strain which would otherwise accumulate in front of the advancing fork.

Topoisomerase I

Topoisomerase inhibitors can be anti-cancer agents (FDA-approved) and include ______ and _______.

topotecan; ironotecan

At the heart of the replicating machinery is _______, which catalyzes synthesis of new DNA using old DNA as a template.

DNA pol

In prokaryotes, there are 3 major DNA pol known, but DNA pol __ is the principal replication enzyme in bacteria.

DNA pol III

DNA pol __ (eukaryotes) is responsible for the priming of replication of both strands.

alpha

DNA pol __ (euk) is responsible for the elongation of both strands.

delta

_________ is a measure of the avg no. of nucleotides added by a DNA pol enzyme per association/disassociation w/ the template.

Processivity

A ______ protein complex is required to keep DNA pol on the template and allow duplicaiton of long stretches of DNA

sliding clamp

In euk, the RNA primers are made at intervals of about ___ nucleotides on the lagging strand, and each primer is ___ nucleotides long.

200; 10

Primers are erased by _________ that recognized an RNA strand in an RNA/DNA helix and excise it; this leaves gaps that are filled by DNA pol III that can proofread.

exonuclease

DNA ligase catalyzes the formation of a _________ bond b/t the 3'-OH end of one fragment and the 5'-P end of the next, linking the sugar-phosphate backbones.

phosphodiester

A thermostable _____ polymerase is used in PCR.

Taq

What are the 3 steps of PCR (in order)?

Denature, anneal, extend

In PCR, annealing is also called___________.

hybridization

PCR primers are short, ssDNA mols that are about __ to __ bps long.

15-40 (primers are shorter in DNA replication)

______ quantifies PCR amplification as it occurs!

RT-qPCR (real time quantitative PCR)

After you amplify DNA, you can determine its sequence using the _______.

Sanger dideoxy chain termination reaction

_____________ automatically analyze DNA molecules label w/ any of 4 diff fluorescent dyes.

Fluorescence protocols

______ are regions of DNA containing tandem copies of di-, tri-, or tetranucleotide repeat units.

Short tandem repeats

STRs make up _____% of the mammalian genome.

10-15

STRs are also called _________.

microsatellites

You need topoisomerase in:
A) replication
B) transcription
C) both

A

The template strand is (sense/antisense), while the non-template strand is (sense/antisense).

anti-sense; sense

The following requires a primer:
a) DNA pol
b) RNA pol
c) both

a

For RNA synthesis to begin, RNA pol must first bind to the dsDNA at specific sequences called ____________.

promoters or promoter regions

In euk, promoters consist of a region -25 to -35 upstream from transcription start site, with a _____________.

TATA consensus sequence (TATA box)

Genes are in inactive states and require __________ to bind to the promoter -- help pol binding, transcription initiation, and expression of protein.

Transcription factors (activators)

In euk, RNA pol II binds a region of DNA (TATA box). _____ and _____ box are also important promoter regions.

CAAT (-80 to -110) and GC (-40 to -50)

In transcription, after about 20-30 nucleotides have been added to the growing RNA chain, a _____ is put on the 5' end.

G-cap (7-methylguanosine)

In transcription, the ___________ protects mRNA from degradation by endonucleases; also assists in binding to ribosome to initiate translation.

G cap

RNA that has just been synthesized is called the __________.

Primary transcript

2 important steps occur before the primary transcript becomes a mature transcript of mRNA that is ready for translation:

1) 3'-polyadenylation (poly-A tail addition) that protects is from exonuclease cleavage.
2) Splicing (removal of introns)

________ is the addition of 100-250 AAAAA to the 3'-end of a primary RNA transcript (coupled to termination)

3'-polyadenylation

Polymerization of aa is a(n) _______ reaction, which creates _______ bonds.

condensation (dehydration); amide (peptide)

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