Background
Macroscopic (systemic) resistance [host–related factors]
Absorption
P-gp
Food
Distribution
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Albumin: Albumin is an important binding protein in the blood. It is a powerful prognostic indicator reflecting diseases’ severity [39, 40], and its prognostic value is subject to gender differences [41]. It has been shown that etoposide is subject to individual variations (Population diversity) changes in the albumin serum concentration and/or age [42, 43].
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Alpha-1-acid glycoprotein (AGP or AAG) sometimes called orosomucoid (ORM) is an acute phase plasma alpha globulin glycoprotein. AGP is a critical determinant factor for the activity of several anticancer agents, e.g. imatinib [44]. Variation of AGP’s serum concentration also affects the anticancer activity of Gefitinib [45]. Wu et al. showed that the γ-secretase inhibitor RO4929097 (Notch signaling blocker) is bound in plasma with high affinity to AGP and can be competitively replaced by GDC-0449 (Hedgehog inhibitor). This consequently increases the availability of potentially active RO4929097 [46]. Therefore, it was suggested that AGP monitoring is critical to predict the pharmacodynamics response to a combined RO4929097/GDC-0449 treatment [46].
Metabolism
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A group of cytochrome P450 (CYP) enzymes responsible for the first step, the introduction of reactive or polar groups into xenobiotic groups [66]. CYP enzymes have been shown to activate some of the anticancer agents [67], as well as inactivate other anticancer drugs [68]. Overexpression of CYP450 in cancer patients might lead to resistance due to the rapid inactivation of the drug. Moreover, the presence of CYP450 shows interindividual variation [69‐71] and so its detection, identification, and quantification prior to starting treatment is essential.
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Glutathione–S–Transferases (GSTs) are endogenous detoxifying enzymes [72] which mediate the second step of drug metabolism [73]. Overexpression of GST correlates with drug resistance [74‐76]. This resistance could occur pharmacokinetically by metabolizing the drugs into inactive molecules [77]. Others suggest this resistance corresponds to detoxification via energy-dependent, transporter-mediated efflux of drugs or drug conjugates from the cell [78]. Also, GST generates resistance by suppressing apoptosis through its ROS-scavenging activity [79, 80] or via MAP kinase inhibition [81]. Conversely, GST is involved in the activation of certain drugs such as γ -Glutamyl- α -amino-(2- ethyl-N, N, N,N- tetrakis (2-chloroethyl) phosphoro-diamidate)-sulfonyl-propionyl)-(R)-(-) phenylglycine (TER286) [65], 6-mercaptopurine (6-MP) [82], and TLK-286 [83]. Because GST shows variability in its expression across populations [84‐87], GST detection prior to chemotherapy could be utilized to inform established therapeutic strategies. Potential GST inhibitors include ethacrynic acid and buthionine sulfoximine [88]. These agents might be consumed concomitantly to keep GST in check in cancer and during cancer therapy. Interestingly, GST is subject to circadian rhythmicity that also affects the activity of 5–fluorouracil (5-FU) and Oxaliplatin [89‐91].
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Extrahepatic metabolism: Typically, the liver plays a major role in drug metabolism. Drug-metabolizing enzymes are also present at other sites e.g. lung, gut, kidney, urinary bladder, skin [92‐95]. Some of anticancer agent is a subjected into extrahepatic metabolism e.g. Oracin [95], and Paclitaxel could be subjected to extrahepatic metabolism too [96]. Extrahepatic metabolism also subjected to interindividual variation [95]. So, this issue should be addressed careful monitoring of these agents should discuss toward individualized chemotherapy [68, 97].
Excretion
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Biliary or bile duct excretion: MDR (ABC) mediates biliary excretion of xenobiotics [98]. Overexpression of ABC is correlated with an increase in biliary excretion [99‐102]. Therefore, careful monitoring of ABC expression should be taken into account when defined anticancer drug is prescribed for the patients and this anticancer drug is knowingly excreted through the bile.
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Renal excretion: The kidney is the primary organ by which drugs are excreted. Interindividual renal drug excretion variability might be due to gender differences [103, 104] and ethnic differences [105]. So, changes in the glomerular filtration rate (GFR) have a direct effect on anticancer drug availability.
Drug–drug interactions
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Agents that target tumor vascularization: tumors require a blood supply for the provision of oxygen and nutrients [107], removal of metabolites [108] and to support metastasis [109]. It is widely assumed that administration of agents that target tumor vasculature (antiangiogenic therapy) eventually interrupts tumor progression. There are two classes of these agents (1) Angiogenesis inhibitors; they inhibit the tumor that has initiated the angiogenic process and (2) vascular disrupting agents that destruct the existing tumor vessels. Those agents might limit perfusion of cytotoxic drugs especially upon chronic administration [110]. Moreover, it is postulated that antiangiogenic therapy is useful in the management of resistance to chemotherapy [111], however, diminishing tumor vascularization may accelerate the adaptation to hypoxia while increasing the necrotic zone by accumulation of metabolites and so worsen tumor prognosis [112]
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Tamoxifen is a prodrug that needs to be metabolized to its active form by CYP2D6, CYP3A, CYP2B6 and CYP2C19 [115]. Some drugs, particularly from the group of selective serotonin reuptake inhibitors, inhibit CYP2D6 and so reduce the efficacy of Tamoxifen by decreasing amount of its active metabolites [116‐118].
Microscopic (local) resistance [tumor related factors]
Evolutionary resistance
Alteration of drug residency in cancer cells
P-gp
MRPs
MXR
Alteration of drug target
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Methotrexate is a drug of choice for the treatment of rheumatoid arthritis [158‐160]. Moreover, its activity against several types of tumors has been shown. It inhibits tumor cells via inhibition of the Dihydrofolate reductase enzyme (DHFR) which is a co-enzyme in DNA-methylation. Both, in vitro and in vivo studies show that the genomic amplification of the DHFR gene is reflected by extra copies of DHFR [161‐163].
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5-fluorouracil is a thymidylate synthetase inhibitor that is widely used in several types of tumors. Thymidylate synthetase is an enzyme used to generate thymidine monophosphate, which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair [164]. It has been postulated that one mechanism of resistance is the gain of extra copies of thymidylate synthetase genes [165, 166].
Microenvironmental resistance
pH
Drugs | pKa | Ionization behavior |
---|---|---|
Daunorubicin | 8.3 | Weak base |
Doxorubicin | 8.3 | Weak base |
Mitoxantrone | 8.3 | Weak base |
Paclitaxel | Zwitterion | |
5-Fluorouracil | 7.76* | Weak acid |
Cyclophosphamide | 6.0 | Weak acid |
Chlorambucil | 5.8 | Weak acid |
Cisplatin | 5.06 | Weak acid |