Introduction in patients. The emergence of chemotherapy resistance

Introduction

Cancer chemotherapy resistance is the primary cause that leads
to an ineffective chemotherapeutic response in patients. The emergence of chemotherapy
resistance can be seen before starting chemotherapy (primary, innate or
intrinsic resistance), or in the course of chemotherapy (Aquired or extrinsic resistance)
1,2,7. Also, chemotherapy failure can arise from factors related to the host 1.
However, researchers focus on figuring out factors related to the tumor that
elicit chemotherapy failure or resistance 1. For example, treatment of Hepatocelular
carcinoma (HCC), multiple myeloma, and breast cancer is difficult due to genetic
or epigenetic changes in cancer cells leading to marked chemotherapy resistance
4,6,7. Resistance mechanisms are abundant and complex 2. The major
mechanism that elicits chemotherapy resistance is the  expression of ATP-binding cassette (ABC)
transporters in a great amount, and that can increase efflux of drugs from cancer
cells, thereby decrease the concentration of the drug inside the cell 3.
Chemotherapy resistance can be divided into three divisions: (1) Macroscopic
(systemic) resistance host–related factors, (2) Microscopic (local) resistance
tumor related factors and (3) Mesoscopic (physical, mechanical) or (regional)
resistance tumor—host interacting factors 1.

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Macroscopic (systemic) resistance host–related factors

For an effective chemotherapy, a chemotherapeutic agent must
reach the tumor 1. Therefore, the pharmacokinetics are an important
host-related factors which have an influence in the chemotherapeutic efficacy
1. If the drug doesn’t reach its target in a sufficient level, we call this
“Pharmacokinetic Resistance”1.

Absorption

Oral administration of the chemotherapeutic agent is better
than intravenous administration, because: (1) There is no hospitalization
required, (2) it prolongs it’s time for clearance, which increase antitumor
activity, (3) it decrease drug toxicity, (4) it enhance patient compliance 1.
However, to maintain a sufficient amount of orally administered chemotherapeutic,
several factors should be taken into consideration 1:

1. P-gp (Permeability glycoprotein)

P-gp is located in the gastrointestinal tract, including the
small intestine where absorption of most anticancer drugs takes place 1. P-gp
overexpression can occur due to genetic polymorphism, pathological condition
and concomitant administration of some anticancer drugs 1. This result in
decreased bioavailability of antineoplastic agent 1.

2. Food

Food can affect absorption and bioavailability of
antineoplastic agent 1. For example, a high-fat meal decreases the rate of
absorption of Topotecan, but it does affect its extent of absorption 1. St
John’s wort, reduces the efficacy of some antineoplastic agent by inducing the
expression of Pregnane X receptor, a xenobiotic or detoxification sensor 1.
Grapefruit juice, decrease the metabolism of antineoplastic agent in the
intestine by reducing the presence of CYP3A4, a metabolizing  enzyme 1.

Distribution

The distribution of the drug between plasma and tissues
depends on several factors 1. Some of them include:

1. Gender

For example, metronidazole has a low volume of distribution
in women 1.

2. Weight

Dose adjustment is needed in cancer patients as they lose
weight because of tumor progression 1.

3. Plasma Proteins

Changes in the plasma concentration of albumin or
Alpha-1-acid glycoprotein result in variable anticancer activity due to binding
of some anticancer agents to these proteins 1.

4.
Circadian rhythm

The best time for administration of anticancer agent is at
night, because the basal metabolic rate is increased at night. This result in
increase activity of anticancer agents since they act against highly
proliferating cells, mainly cancer cells 1.

Metabolism

Drug metabolism is different from anabolism and catabolism
1. Its main role is detoxification or activation of drugs 1.

·       
CYP450 (Cytochrome P450) Enzymes, can activate some
antineoplastic agent, as well as inactivate them 1. Overexpression of CYP450
in cancer patients might lead to resistance due to the rapid inactivation of
antineoplastic agent 1.

·       
GSTs (Glutathione–S–Transferases), overexpression of
GSTs in cancer patients might lead to resistance 1. It is involved in drug
inactivation and apoptosis suppression 1.

·       
Extrahepatic metabolism: anticancer agent inactivation
can occur in the lung, gut, kidney, urinary bladder and skin 1.

Excretion

Excretion of anticancer agent occurs through two main routes:
biliary and renal excretion 1.

·       
Biliary or bile duct excretion: Overexpression of ABC
increase the biliary excretion of anticancer agent 1.

 

·       
Renal excretion: an increase in the glomerular
filtration rate (GFR) reduces the availability of anticancer drug 1.

Combination Therapy

Administration of a single chemotherapeutic agent is not
effective. Since, high concentration of the agent is needed, plus it causes
more toxicity, increase the likelihood of resistance and attack only single
population of tumor (a tumor consists of a heterogeneous population) 1.
However, using a combination of chemotherapeutic agents is effective. Since, it
decreases the required concentration for each agent, decreases the side
effects, decreases the likelihood of resistance and attack several population
of the tumor 1.

Microscopic (local) resistance tumor related factors

Ineffective chemotherapy can occur due to failure at the
tumor site 1. This happens by several mechanisms. Some of them are:

Evolutionary resistance

Also called acquired resistance, extrinsic resistance, active
resistance, or biochemical resistance 1. Evolutionary resistance could occur
either through manipulating drug resident time inside the cell and/or modifying
its site of action 1.

1. Alteration of drug residency in cancer cells

Proteins are the main reason for altering drug residency in
cancer cell, including:

·       P-gp: also called multidrug resistance
protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or
cluster of differentiation 243 (CD243) 1. P-gp also induces expression of CYP3A4 that in turn may
deactivate some antineoplastic agent 1. Expression of P-gp fluctuates with
increased expression level in untreated cancer into higher level upon relapse
after chemotherapy and undetectable or decreased level in the expression in
drug sensitive tumors 1.

·       
MRPs (Multidrug resistance-associated protein): The MRP family consists of the four
isoforms MRP1, MRP2, MRP3 and MRP4 1 . MRPs are similar to P-gp in that they
are (1) capable of lowering intracellular drug levels and (2) ATP-dependent 1.

·       
MXR (Mitoxantrone resistance protein): also called Multixenobiotic resistance protein, BCRP, ABCP and ABCG2, is one member of
the ABC-superfamily that plays a role in trafficking biological molecules
across cell membranes 1. Expression of MXR can be an alternative strategy of
resistance if cancer cells lack p-gp and MRP 1.

2. Alteration of drug target

Another mechanism of resistance may emerge when the drug
arrives at its site of action. 1. This type of mechanism of resistance can be
made clear by these examples:

·       
DNA topoisomerase II mutations result in resistance to
drugs that act on this enzyme such as doxorubicin and etoposide 8.

·       
Dihydrofolate reductase amplification result in
resistance to drugs that act on this enzyme such as methotrexate 9.

Microenvironmental
resistance

Cancer cells have different microenvironment than normal
cells. For example, the pH is less than seven extracellularly and more than seven
intracellularly 1. Due to the different microenvironment that cancer cells
posses, they have the capacity to decrease immunity, stop normal cell growth and
prevent drugs entry to cancer cells. 1. There are three important components
of cancer cell microenvironment that grant drug restriction 1:

·       
pH

Anticancer agent undergoes “ion
trapping mechanism”, where weakly basic anticancer agents partitioning to
cancer cells are decreased due to its ionization at the interstitial fluid and
their incorporation into the lysosomes after they cross the plasma membrane 1.
And, where weakly acidic anticancer agents partitioning to cancer cells are
increased and rendered after they cross the plasma membrane, slightly prevented
from reaching the target site 1.

·       
Oxygen

Hypoxia causes chemotherapy resistance by eliminating the presence of
free radicals, which is important to initiate apoptosis of cancer cells 1.

·       
Glucose

Hyperglycemia may have an impact on
the effectiveness of chemotherapy 5.

 

 

 

 

Mesoscopic (physical, mechanical) or (regional) resistance
tumor—host interacting factors

Blood vessel morphology and blood viscosity at tumor site
affect chemotherapy efficacy 1. Increase vascular resistance and blood
viscosity results in a decrease of the amount of anticancer agent reaching
their target site and vice versa 1.