IntroductionCancer chemotherapy resistance is the primary cause that leadsto an ineffective chemotherapeutic response in patients.
The emergence of chemotherapyresistance can be seen before starting chemotherapy (primary, innate orintrinsic 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 thatelicit chemotherapy failure or resistance 1. For example, treatment of Hepatocelularcarcinoma (HCC), multiple myeloma, and breast cancer is difficult due to geneticor epigenetic changes in cancer cells leading to marked chemotherapy resistance4,6,7. Resistance mechanisms are abundant and complex 2. The majormechanism 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 cancercells, 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) resistancetumor related factors and (3) Mesoscopic (physical, mechanical) or (regional)resistance tumor—host interacting factors 1. Macroscopic (systemic) resistance host–related factorsFor an effective chemotherapy, a chemotherapeutic agent mustreach the tumor 1. Therefore, the pharmacokinetics are an importanthost-related factors which have an influence in the chemotherapeutic efficacy1. If the drug doesn’t reach its target in a sufficient level, we call this”Pharmacokinetic Resistance”1.AbsorptionOral administration of the chemotherapeutic agent is betterthan intravenous administration, because: (1) There is no hospitalizationrequired, (2) it prolongs it’s time for clearance, which increase antitumoractivity, (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 thesmall intestine where absorption of most anticancer drugs takes place 1.
P-gpoverexpression can occur due to genetic polymorphism, pathological conditionand concomitant administration of some anticancer drugs 1. This result indecreased bioavailability of antineoplastic agent 1.2.
FoodFood can affect absorption and bioavailability ofantineoplastic agent 1. For example, a high-fat meal decreases the rate ofabsorption of Topotecan, but it does affect its extent of absorption 1. StJohn’s wort, reduces the efficacy of some antineoplastic agent by inducing theexpression of Pregnane X receptor, a xenobiotic or detoxification sensor 1.
Grapefruit juice, decrease the metabolism of antineoplastic agent in theintestine by reducing the presence of CYP3A4, a metabolizing enzyme 1.DistributionThe distribution of the drug between plasma and tissuesdepends on several factors 1. Some of them include:1. GenderFor example, metronidazole has a low volume of distributionin women 1.2. WeightDose adjustment is needed in cancer patients as they loseweight because of tumor progression 1.
3. Plasma ProteinsChanges in the plasma concentration of albumin orAlpha-1-acid glycoprotein result in variable anticancer activity due to bindingof some anticancer agents to these proteins 1.4.Circadian rhythmThe best time for administration of anticancer agent is atnight, because the basal metabolic rate is increased at night. This result inincrease activity of anticancer agents since they act against highlyproliferating cells, mainly cancer cells 1.
MetabolismDrug metabolism is different from anabolism and catabolism1. Its main role is detoxification or activation of drugs 1.· CYP450 (Cytochrome P450) Enzymes, can activate someantineoplastic agent, as well as inactivate them 1. Overexpression of CYP450in cancer patients might lead to resistance due to the rapid inactivation ofantineoplastic agent 1.· GSTs (Glutathione–S–Transferases), overexpression ofGSTs in cancer patients might lead to resistance 1.
It is involved in druginactivation and apoptosis suppression 1.· Extrahepatic metabolism: anticancer agent inactivationcan occur in the lung, gut, kidney, urinary bladder and skin 1.ExcretionExcretion of anticancer agent occurs through two main routes:biliary and renal excretion 1.· Biliary or bile duct excretion: Overexpression of ABCincrease the biliary excretion of anticancer agent 1. · Renal excretion: an increase in the glomerularfiltration rate (GFR) reduces the availability of anticancer drug 1.Combination TherapyAdministration of a single chemotherapeutic agent is noteffective.
Since, high concentration of the agent is needed, plus it causesmore toxicity, increase the likelihood of resistance and attack only singlepopulation of tumor (a tumor consists of a heterogeneous population) 1.However, using a combination of chemotherapeutic agents is effective. Since, itdecreases the required concentration for each agent, decreases the sideeffects, decreases the likelihood of resistance and attack several populationof the tumor 1.
Microscopic (local) resistance tumor related factorsIneffective chemotherapy can occur at the tumor site 1.This happens by several mechanisms. Some of them are:Evolutionary resistanceAlso called acquired resistance, extrinsic resistance, activeresistance, or biochemical resistance 1. Evolutionary resistance could occureither through manipulating drug resident time inside the cell and/or modifyingits site of action 1.1. Alteration of drug residency in cancer cellsProteins are the main reason for altering drug residency incancer cell, including:· P-gp: also called multidrug resistanceprotein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) orcluster of differentiation 243 (CD243) 1.
P-gp also induces expression of CYP3A4 that in turn maydeactivate some antineoplastic agent 1. Expression of P-gp fluctuates withincreased expression level in untreated cancer into higher level upon relapseafter chemotherapy and undetectable or decreased level in the expression indrug sensitive tumors 1.· MRPs (Multidrug resistance-associated protein): The MRP family consists of the fourisoforms MRP1, MRP2, MRP3 and MRP4 1 .
MRPs are very much alike to P-gp being(1) able to decrease drug concentration inside the cell and (2) ATP-dependent1.· MXR (Mitoxantrone resistance protein): also called Multixenobiotic resistance protein, BCRP, ABCP and ABCG2, is one member ofthe ABC-superfamily that is involved in exchanging biological molecules acrosscell membranes 1. If cancer cells don’t have P-gp and MRP to elicitchemotherapy resistance, expression of MXR can be a substitute strategy 1.2.
Alteration of drug targetAnother mechanism of resistance may emerge when the drugarrives at its site of action. 1. This type of mechanism of resistance can bemade clear by these examples:· DNA topoisomerase II mutations result in resistance todrugs that act on this enzyme such as doxorubicin and etoposide 8.· Dihydrofolate reductase amplification result inresistance to drugs that act on this enzyme such as methotrexate 9.
MicroenvironmentalresistanceCancer cells have different microenvironment than normalcells. For example, the pH is less than seven extracellularly and more than sevenintracellularly 1. Due to the different microenvironment that cancer cellsposses, they have the capacity to decrease immunity, stop normal cell growth andprevent drugs entry to cancer cells. 1.
There are three important componentsof cancer cell microenvironment that grant drug restriction 1:· pHAnticancer agent undergoes “iontrapping mechanism”, where weakly basic anticancer agents partitioning tocancer cells are decreased due to its ionization at the interstitial fluid andtheir incorporation into the lysosomes after they cross the plasma membrane 1.And, where weakly acidic anticancer agents partitioning to cancer cells areincreased and rendered after they cross the plasma membrane, slightly preventedfrom reaching the target site 1.· OxygenHypoxia causes chemotherapy resistance by eliminating the presence offree radicals, which is important to initiate apoptosis of cancer cells 1.· GlucoseHyperglycemia may have an impact onthe effectiveness of chemotherapy 5. Mesoscopic (physical, mechanical) or (regional) resistancetumor—host interacting factorsBlood vessel morphology and blood viscosity at tumor siteaffect chemotherapy efficacy 1. Increase vascular resistance and bloodviscosity results in a decrease of the amount of anticancer agent reachingtheir target site and vice versa 1.