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Resistance to Cancer Chemotherapy Alfarouk et al. Cancer Cell Int (2015) 15:71 DOI 10.1186/s12935-015-0221-1 REVIEW Open Access Resistance to cancer chemotherapy: failure in drug response from ADME to P‑gp Khalid O Alfarouk1*, Christian‑Martin Stock2, Sophie Taylor3, Megan Walsh3, Abdel Khalig Muddathir4, Daniel Verduzco5, Adil H H Bashir1, Osama Y Mohammed6, Gamal O Elhassan7,8, Salvador Harguindey9, Stephan J Reshkin10, Muntaser E Ibrahim1 and Cyril Rauch3 Abstract Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer. Keywords: Drug, Resistance, Pharmacokinetics, ADME, pH, MDR Background Macroscopic (systemic) resistance [host–related In US only, the newly diagnosed cancer patient is factors] 1,665,540 every year and the estimated death is 585,720 One of the major effects of host-related factors that [1] which are increasing as countries become more devel- determine the activity of the drug is pharmacokinetic. oped and more people reach advanced ages. Therefore, Pharmacokinetics is defined as the action of the body in many efforts are being done in the war against cancer [2]. response to drug and can be divided into the following One of these efforts is the continuous development of consecutive steps: Absorption, Distribution, Metabo- new drugs and forms of chemotherapy. lism and Excretion (ADME) [4]. Here we introduce the In cancer, chemotherapy represents the backbone concept of “Pharmacokinetic Resistance” to describe the of treatment for many cancers at different stages of the body-related factors that alter the effectiveness of the disease. Therefore, chemotherapeutic resistance results drug, so that it either does not reach its target and/or in therapeutic failure and usually, (eventually) death. To cannot accomplish its intended goal. Chemotherapeutics address these limitations, many researchers focus on how must be in contact with the tumor. cancer cells manipulate their genomes and metabolism to prevent drug influx and/or facilitate efflux of accumu- Absorption lated drugs, the so called: “the neostrategy of cancer cells There are growing evidences suggesting that orally can- and tissues” [3]. In this work, we show that drug resist- cer chemotherapy is preferable to intravenous admin- ance is a multifactorial phenomenon that requires atten- istration, because: (1) it is low-cost from the national tion to the host as well as the tumor and that such factors health services perspective (i.e. does not require hospi- are organized at different levels (Figure 1). talisation), (2) it can increase the drug’s antitumor activ- ity by prolonging it’s time to clearance [5], (3) it reduces drug toxicity [6], (4) increase patients’ compliance and improve pharmacoeconomic issues [7–9]. However, to maintain a sufficient amount of orally administered *Correspondence: Alfarouk@Hala‑Alfarouk.org 1 Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan chemotherapeutics, several factors should be taken into Full list of author information is available at the end of the article consideration: © 2015 Alfarouk et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Alfarouk et al. Cancer Cell Int (2015) 15:71 Page 2 of 13 P-gp Absorpon Food Distribuon Macroscopic level (Systemic) Metabolism Excreon P-gp ance Alteraon of drug MRPS residency in cancer cell sist Evoluonary Resistance Re Alteraon of drug target MXR Microscopic level (Local) pH Mesoscopic level Microenvironmental (Regional) Oxygen Resistance Glucose Figure 1 Diagrammatic representation describes that cancer chemotherapy resistance is a multi‑factorial phenomenon that could be organized as multilevel structure. P‑gp xenobiotic or detoxification sensor, which reduces the Permeability glycoprotein (P-gp), also known as multi- efficacy of some antineoplastic agents, e.g. Irinotecan drug drug resistance protein (MDR) is found along the [4]. CYP3A4 is a metabolising enzyme (see below) which gastrointestinal tract (GIT) [10], including the small has been found in the intestine presumably as a defense intestine as primary site for the epithelial absorption of strategy against xenobiotics [20]. It is well known that many orally administered drugs [11]. It has been shown grapefruit juice abates the presence of CYP3A4, which is that P-gp reduces the oral bioavailability of some anti- beneficial for the application of antineoplastic oral agents cancer drugs [12]. Concomitant administration of some with low bioavailability [21]. Thus, it becomes apparent of the antineoplastic agents leads to the overexpression that the interaction between food and antineoplastic of P-gp that results in bioavailability reduction of several agents should be cautiously monitored to maintain a suf- these agents, e.g. Imatinib [13]. P-gp expression, in the ficient bioavailability [22–24]. gut, is a subject of interindividual variation due to either genetic polymorphism or pathologic condition [14, 15] Distribution and so fluctuates the bioavailability of several antineo- The “volume of distribution” (Vd) of the drug is a hypo- plastic agents e.g. paclitaxel [12]. thetical volume that outlines drug distribution into tis- sues [25, 26]. A higher Vd means that more of a drug Food penetrates into a tissue while it is more diluted (present The effects of food on drug absorption and bioavailability at lower concentrations) in the plasma. The distribution have been attracting attention very much and stimulated of the drug between plasma and tissues relies on several a long debate of whether fasting improved or worsened factors. Some of them include: a drug’s bioavailability [16–18]. It has been shown that the half-life period of orally applied Topotecan is longer 1. Gender Metronidazole, a bactericide and protozoo- than that of intravenous administration. The adminis- cide, also displays a potential activity as an antican- tration of Topotecan with a high-fat breakfast shows a cer drug, especially as a radiosensitizer in hypoxic small decrease in the absorption rate but does not affect regions [27], and shows a lower Vd in women [28] the extent of the absolute absorption [19]. St John’s Furthermore, women are subject to pharmacokinetic wort, induces the expression of Pregnane X receptor, a variability during their menstrual cycle [29]. There- Alfarouk et al. Cancer Cell Int (2015) 15:71 Page 3 of 13 fore, it is critical to consider the gender factor also to [47]. The circadian rhythm has been implicated in age if the concentration of the drug in the plasma is the pathophysiology of several diseases [48–50], drug to be determined or needs to be defined. action [51, 52] and pharmacokinetics of drugs as well 2. Weight Weight is a paramount factor that determines [53–55]. Plasma protein levels reach their minimum dose adjustment [30]. Cancer patients often lose around 4:00 a.m. and start to increase around 8:00 weight during tumor progression [31–33]. Therefore, a.m. [56]. This circadian rhythm can be masked at dosing based on body weight should be routinely re- younger ages, but it aggravates and becomes clearer adjusted to the current weight [34, 35]. with aging [56]. Therefore, proper dosage timing 3. Plasma proteins when a drug is available in the blood should result in higher drug concentrations reaching (plasma), the drug will be found either in free or the tumor site. It has been shown that alpha one acid bound form to plasma proteins (see Figure 2). Albu- glycoprotein (AGP) is subject to circadian rhythms min and Alpha 1-acid glycoprotein are an example of [57]. In cancer, it has been demonstrated that Cis- drug-binding plasma proteins. While albumin carries platinum shows a considerable variability in its bind- acidic drugs, the alpha 1-acid glycoprotein will carry ing capacity day and night [58, 59]. Thus, circadian basic and neutral lipophilic drugs [36–38]. rhythmicity has a significant impact on a drug’s phar- macophore i.e. the active site of the drug molecule, • Albumin: Albumin is an important binding pro- and a delicate balancing between chronotolerability tein in the blood. It is a powerful prognostic indi- (minimum toxicity to host) and chronoefficacy (max- cator reflecting diseases’ severity [39, 40], and its imum cytotoxicity) is required [60]. Moreover, most prognostic value is subject to gender differences of currently used anticancer agents act against highly [41]. It has been shown that etoposide is subject proliferating cells, and since the basal metabolic rate to individual variations (Population diversity)
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