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cancer treatment is divided into four
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main types surgical radiation therapy
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chemotherapy and biologic therapy now
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the goal of cancer treatment is to
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eradicate the cancer every cancer
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treatment has the potential to cause
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harm and treatment may be given that
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produces toxicity with really no benefit
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in this video we're gonna talk about
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chemotherapy agents and their mechanism
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of action chemotherapy agents have
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different mechanism action and target
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different parts of the cell cycle
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combinations of these chemotherapy
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agents are preferred because different
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mechanism action means that they work on
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different parts of the cell cycle which
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means that overall less side effects in
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order to understand how chemotherapy
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drugs chemotherapy agents work we
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firstly have to revise the cell cycle
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the cell cycle has four phases the
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growth one phase or the g1 phase where
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the organelles duplicate the S phase
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which is where the DNA basically
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replication occurs the growth 2 phase is
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when the cell prepares itself for the M
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phase which is mitosis where the cell
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divides into two identical daughter
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cells then the cell cycle will repeat
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itself we can further explore mitosis
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mitosis has other phases the prophase is
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where the centrosome duplicates and form
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these microtubules in metaphase the
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chromosomes the DNA really align in the
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middle of the cell and the microtubules
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that were formed from the centrosome
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attach to the centromeres which are the
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center points of the chromosomes in
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anaphase the chromosomes are separated
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and reach either end of the cell in
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chilla phase the cell membrane
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constricts ready to separate and then a
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new nuclear membrane
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is being formed the cell cycle is a
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continuous process and so you have
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checkpoints during the cell cycle to
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make sure that there are no
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abnormalities in the cell before it
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progresses to each phase these
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checkpoints include the g1 checkpoint
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the g2 checkpoint and the M phase
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checkpoint one thing these checkpoints
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look at is whether there are
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abnormalities damage or mutations to the
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DNA for example DNA is a double helix
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structure composed of four nucleotides
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after the g1 phase where the organelles
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are duplicate comes the S phase now in
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the S phase DNA becomes replicated now
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let's revise this process during
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replication the DNA strand is separated
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by an enzyme called helicase during the
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unwinding of DNA tension can occur
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distally the tensions are these coils
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that are being formed the cells have a
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normal biological mechanism to fix these
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coils and super coils that are being
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formed this mechanism is an enzyme
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called topoisomerase here topoisomerase
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to fixes these super coils reducing the
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tension in the DNA strand and we'll talk
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about topoisomerase later on now there
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are four types of nucleotides as
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mentioned in DNA these nucleotides can
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be divided into two groups pyrimidine
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and purine pyrimidine includes thymine
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and cytosine and purines include adenine
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and guanine so what happens is a
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double-stranded DNA gets unwind by
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helicase into two separate strips
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another enzyme called DNA polymerase
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will create a new strand on both strips
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the new strand following the helicase is
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the leading strand the lagging strand is
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the Strand that is created in segments
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chemotherapy agents target different
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parts of the cell cycle as mentioned
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because of this they are grouped into
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different classes let's take a look at
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the different classes one at a time
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first let's begin with alkylating agents
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the oldest anti-cancer cytotoxic s-- now
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these agents are antiproliferative drugs
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they work by binding covalently via
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alkyl groups to DNA they then form cross
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links and thought to arrest the cell
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cycle in the g1 or the S phase of the
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cell cycle
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now the alkylating agents actually bind
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to the nucleotide guanine once bound
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they form cross linkage of DNA strands
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broken or cross-linked DNA is
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intrinsically unable to complete normal
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replication or cell division so they
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undergo cell arrest they stop because
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they're in cell arrest the cell will
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then either be repaired so it can
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proceed progress through the cell cycle
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or this cell will undergo apoptosis
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basically dying examples of drugs in the
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class of alkylating agents include
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nitrogen mustards such as
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cyclophosphamide and there's also
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cisplatin now cisplatin
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is an interesting drug it is one of the
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most active anti-cancer drugs and used
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on many types of cancers but also come
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with many toxicities it is it is
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actually its own class but has similar
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mechanism of action to alkylating agents
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and so it is put in this category the
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next class of chemotherapy agents are
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the anti metabolites or the
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antimetabolites these guys interfere
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with normal cell metabolism of nucleic
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acids so really they disrupt DNA RNA
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metabolism production interrupting the S
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phase of the cell cycle we will focus on
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DNA metabolism here and the four
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nucleotides for DNA are thymine cytosine
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adenine and guanine of which thymine is
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strictly DNA
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I mean the DNA nucleotide is made after
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a series of reactions one important
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reaction is from D UMP to D TMP this
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reaction is carried out by an enzyme
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called fireman delayed synthase for D
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UMP to convert to dtmp requires a
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co-current reaction which phiman delayed
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synthase also carries out this is the
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conversion between methylene
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tetrahydrofolate to dihydrofolate so
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Thermolite synthase catalyzes methylene
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tetrahydrofolate and D UMP to form
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dihydrofolate and the TMP dihydrofolate
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is converted to tetrahydrofolate by
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another important enzyme dihydrofolate
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reductase
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tetrahydrofolate becomes methyl
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tetrahydrofolate once again so this
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whole reaction involving these two
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enzymes thermo delayed synthase and
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dihydrofolate reductase it's important
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in order to make DNA by interrupting any
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of these two enzymes you are essentially
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disrupting thymine thymidine synthesis
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and thus DNA synthesis a few
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chemotherapy agents work here
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these include five floral uracil which
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inhibits the mid-late synthase and also
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specific time a delayed synthesis
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inhibitors a very common drug used in
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rheumatoid arthritis also is a
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chemotherapy drug and an ectopic
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pregnancy drug this drug is methotrexate
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and it works by inhibiting
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dihydrofolate reductase other
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chemotherapy agents that work
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specifically on disrupting purine
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metabolism and synthesis include or
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CAPTA purine and theö guanine here in
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summary antimetabolites work by
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disrupting DNA RNA metabolism and
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production and thus it will disrupt
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cancer cells from progressing through
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the cell cycle
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the next class are anti-tumor
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antibiotics main ones include a group
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called anthracyclines these antibiotics
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have several mechanism of action but
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their specific mechanism action is
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unclear
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one effect is at these anti-tumor
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antibiotics inhibits topoisomerase to
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remember topoisomerase are important
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enzymes in maintaining the structure
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that topology of DNA topoisomerase to
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remember relaxes super coils by breaking
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two DNA strands unwinding it relaxing it
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and then attaching it back together once
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it's unwound and so by inhibiting
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topoisomerase DNA doesn't relax and so
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replication becomes hard with the super
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coils or maybe the topoisomerase breaks
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the DNA strand but then can't really
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attach it back together
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either way DNA replication is inhibited
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and the cell doesn't progress through
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the cell cycle another way antibiotics
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work is by inhibiting helicase the
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enzyme which unwinds the DNA by
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inhibiting this enzyme you inhibit DNA
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replication finally antibiotics such as
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anthracyclines induce reactive oxygen
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species formation causing destruction of
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the cell and triggering apoptosis
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examples of anthracyclines include
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doxorubicin and donor ribbon
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the next class of chemotherapy drugs are
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the topoisomerase inhibitors
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topoisomerase remember our essential
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enzymes in regulating the topology of
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DNA helix there are two types of
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topoisomerase there's top are summaries
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one and there's topoisomerase to which
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we have already talked about
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topoisomerase one cleaves only one
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strand of the DNA and relaxes DNA coil
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during replication example is here is a
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DNA double helix the top where somewhere
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is one will click one strand
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and then unwind it and attach it causing
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one less coil topoisomerase to as
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mentioned cleaves two strands of the DNA
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helix and relaxes supercoils during DNA
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replication which again we've already
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talked about topoisomerase one
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inhibitors inhibit topoisomerase one and
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thus inhibits the relaxation of DNA and
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thus potentially inhibits proper DNA
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replication example of this chemotherapy
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agent is cam 2 thus in topoisomerase two
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inhibitors we already talked about and
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include etoposide
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you
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the next chemotherapy class work on the
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M phase of the cell cycle and are called
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the anti microtubule agents these guys
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disrupt the M phase of the cell cycle
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leading to cell arrest which then will
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lead to apoptosis these are the taxanes
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and the vinca alkaloids let's just
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quickly recap the M phase to understand
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how these anti microtubule agents work
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the M phase consists of the prophase
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metaphase anaphase and telophase during
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early mitosis microtubules are extending
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from the centrosomes and attach to the
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centromeres of the chromosome the
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microtubules allow for the separation of
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duplicated DNA into either side of the
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cell before the microtubules start
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degrading and breaking down vinca
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alkaloids inhibit microtubule assembly
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or formation and so are known as
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microtubule destabilizes without no
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microtubules forming this will disrupt
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the M phase causing cell arrest
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the other group of anti microtubules are
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the taxanes these guys bind to and
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stabilize the microtubules that are
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already formed in the M phase and so
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these guys are called the microtubule
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stabilizers they basically inhibit the
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breakdown of the microtubules once they
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are formed and so you don't complete the
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M phase of the cell cycle which means
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you get M phase arrest you get cell
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arrest the other important class of
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chemotherapy agents are the hormonal
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agents which are not discussed here
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because there are many times hopefully a
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separate video will look into this thank
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you for watching I hope this helped
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thank you for watching finally it's very
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important to understand the side effects
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of chemotherapy agents I have a separate
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video on that which looks at the side
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effects the acute side effects of
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chemotherapy agents thank you for
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watching
