The metabolizing the drugs into inactive form

 

The chemotherapeutic failure  or on the other name  chemotherapeutic resistance : is  acquired ability of host cells to evade the
effects of chemotherapeutics and is one of the most pressing major  trouble in chemotherapy . Chemotherapy
resistance can be due to several factors,  firstly host -related factors. The second one
is tumor related factor,  which is  genes that reflected the effect of
chemotherapeutic by  efflux pump
mechanism that handle the expression of drug  and most study focused on it . In this work, there
are factors that related to failure of chemotherapy or causes the resistance of
chemotherapeutic drugs.

host–related
factors

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

Reference

 Pharmacokinetic
variability of anticancer agents. Gomez-Abuin G, Ratain MJ

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-gp can
reflected the chemotherapeutic effect by reducing the oral bioavailability of
drugs . this is by overexpression of P-gp that results in bioavailability
reduction of several these agents. 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 .

References

Paxton JW The effect of food on the
bioavailability and kinetics of the anticancer drug

 

Metabolism

There
are 2 steps of drug metabolism , the first step is  involve reactions of hydroxylation or
oxidation. metabolism enzymes such as cytochrome P450 and glutathione
S–transferase could be inactivate certain anticancer drugs. Introduction of
reactive or polar groups into xenobiotic groups occur by CYP450 enzyme.  Overexpression of CYP450 in cancer patients
might lead to resistance due to the rapid inactivation of the drug. Glutathione
S Trans-ferase  also another enzyme that
could contribute the resistance of chemotherapy. it responsible in the second
step of drug metabolism, the resistance occur when overexpression of this
enzyme (same CYP450) . This resistance could occur by metabolizing the drugs
into inactive form .

Reference

NPE Enzyme-catalyzed activation of
anticancer pro-drugs. Rooseboom M, Commandeur JNM, Vermeulen

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  .

 

Reference

The effects of race or ethnicity on
pharmacokinetics of drugs. johnson JA

 

Drug–drug interactions

Usually , the combination of  chemotherapy is useful in treating infection
. Conversely, it sometimes that co-administration of drugs may result in antagonism,
one drug may counteract or neutralize another one.  sodium bicarbonate has been recently used
systemically in the treatment of cancer. by induces systemic alkalosis. it can
enhance methotrexate excretion By elevation of urine pH. Therefore, sodium bicarbonate
modulates the pharmacokinetics of methotrexate. 
Tamoxifen is another drug that can decreased their activity by drug-drug
interaction . it is a  pro-drug that
needs to be metabolized to its active form by CYP2D6 and other . Some drugs,
particularly from the group of SSRI, inhibit CYP2D6 and so reduce the efficacy
of Tamoxifen by decreasing amount of its active metabolites. A combination of clindamycin
and macrolides drug class can antagonize each other.

Reference 

Pharmacokinetic drug interactions
with anticancer drugs. Loadman PM, Bibby MC

 

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.

 

Reference

Antibiotic resistance is prevalent in
an isolated cave microbiome. Banks
ED, Johnston MD et al

 

 

 

Altering drug site

it is occur when the drug reached its
target, . Methotrexate is an examples, which explain this mechanism of
resistance, it is a drug of choice for the treatment of several types of tumors.
The mechanism of 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,  Fluorouracil  is an example which can reflected their effect
by altering the site of it. The MOA IS  thymidylate synthetase inhibitor and it used in
several types of tumors. It has shown  that the more production or gain of extra copies
of thymidylate synthetase can  contribute
the mechanism of resistance to the drug.

Reference

Cellular localization of the
multidrug-resistance gene product P-glycoprotein in normal human tissues.
Thiebaut F, Tsuruo T, Hamada H, Gottesman MM

 

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
deactivate some chemotherapy (cyclosporin,Tamoxifen). This is explain the
altering drug residency

Reference

Unstable methotrexate resistance in
human small-cell carcinoma. Bailey BD, Drake JC et al

 

 

Microenvironmental
resistance (Trapping mechanism)

The micro environmental of the
tumor  can make failure to chemotherapeutic.
By reducing the activities of the  chemotherapeutic agents this lead to  causing  fail 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 can be 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 by clonal tumor
expansion or  tumor. This is called interacting
of humor- host factor

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