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The chemotherapeutic failure  or on the other name  chemotherapeutic resistance : is  when the host cellcan evade (resist)the
effects of chemotherapeutic agent. It is the most important problem in
chemotherapy. Chemotherapy resistance can bedivided into 2 main factor: firstly,host
-related factors. The second one is tumor related factor,which is reflected the
effect of chemotherapeutic by the mechanism ofefflux- pump that handle the
expression of drug .

Host Related
factors

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A host-related
factors that can determine the activity of the drug is called pharmacokinetic.
it is defined as the what body do to the drug and can be divided into 4 rotation
:absorption, distribution, metabolism and excretion (ADME). The host mechanism
thatreflected  the effectiveof chemotherapeutic
drug, by prevent reaches its target or prevent to  fulfill its intended goal is
“Pharmacokinetic resistance ” . (Drugs  must targetthe tumor site to kill the
micro-organism).

 

Absorption
: it can reduce  the effect  of the drug by reducing the bioavailability
of it. Then, cause failure of drug effect this occur by permeability
glycoprotein that found in  (GIT)including the small intestine. P-gpcan
reflected the chemotherapeutic effect by reducing the oral bioavailability of
drugs . Reduction bioavailability of these agents results by over – expression
of P-gp. Also, food is another  example which can affect the drug absorption
and bioavailability. Highly fat meal can affect the drug bioavailability and
decrease the affect .

 

 

 

 

 

Metabolism

Metabolism
could be  in two phases (hydroxylation or
oxidation). This is by 2 enzymes CYP450 and GST enzymes. Inserting a polar
groups into xenobiotic occur by CYP450 enzyme. 
The resistance occur by in-activation the drug by over- expression of
CYP450. In the same way GST enzyme can contribute the resistance of
chemotherapy. it responsible in the second step of drug metabolism, the
resistance occur when over expression of this enzyme. This resistance could
occur by metabolizing the drugs into inactive form .

Excretion

It is the final rotation of the drug
in the body . it can by two mechanism : biliary and renal excretion.  The change rate of glomerular filtration rate
(GFR) can effect of drug availability and bioavailability which can contribute
to the resistance of chemotherapeutic  .

 

Drug–drug interactions

Usually , the combine of two or more
of chemotherapy is good in treat the infection. Conversely, it sometimes that
co-administration of drugs may lead to antagonism, one drug may counteract the
other one.Lately,Sodium bicarbonate has been used systemically in the treatment
of cancer. By induces systemic alkalosis, it can enhance methotrexate excretion
by elevation of urine pH. Tamoxifen is another drug that can decreased their
activity by drug-drug interaction . it needs to be metabolized to its active
form by CYP2D6 and. The selective serotonin reuptake inhibitor group  inhibit CYP2D6 this lead to reduce the
efficacy of Tamoxifen by decreasing amount of its active metabolites. A
combination of clindamycin and macrolides drug class can antagonize each other.

 

Tumor
related factors

Sometime the failure of chemotherapy
to treat associated with the tumor site. Could be by Evolutionary resistance
or  acquired resistance .The resistance
that can be found in bacteria due to exposure to antibiotics is called  acquired resistance. it  could be either through altering its site of
action or interfering with drug resident.

 

Altering drug site

it is occur when the drug reached its
target lead to altering the site of drug which lead then to the resistance .the
example is methotrexate.It isa drug of choice for the treatment of several
types of tumors. The mechanismof methotrexate inhibition of the dihydrofolate
reductase enzyme (DHFR) this inhibition of the DHFR lead to inhibit the tumor
cells. Researches  show that the DHFR can
reflected the methotrexate by generating extra copy of its  which means that producing  more copy of dihydrofolate reductase enzyme.
Also, there is another example which can reflected their effect by altering the
site of it. Fluorouracil which its MOA is thymidylate synthetase inhibitor and
it used in several types of tumors. It hasshown  that the more production of extra copies of that
enzyme can  contribute the resistance to
the drug.

 

Alteration of drug residency in
cancer cells

P-glycoprotein It is a glycoprotein
which  is localized at the plasma
membrane  of colon, jejunum, bile
canaliculi and the other . it is consider as enzyme inducer of CYP3A4. This
expression of CYP3A4 can decreased the activity of some chemotherapeutic such
as (cyclosporin,Tamoxifen). This is explain the altering drug residency.

 

 

 

 

 

Microenvironmental
resistance (Trapping mechanism)

The micro environmental of the
tumor  can make failure to chemotherapeutic
by reducing the activities of itthis lead to causingfail in responses of the
drug. This is by two mechanism :one of it  through disturbing drug partitioning, the
second is  through induction of multi
drug resistance expression. It is prevented chemotherapeutic to reaching their
targets site . Because the  weakly acidic
drugs increase their dividing  into the
interstitial fluid, which is alkaline media this  prevented from reaching their targets.

chemotherapy could impacted  their activity and contribute in drug
resistance by the physics of the tumor site. There are 2 mechanism in which Tumor
can decreased the amount of drug to reaching its target either byclonal tumor
expansionorby the tumor perfusion . This is called interacting of humor- host
factor

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