Sabina Dizdarevic • A. Michael Peters
Treatment of patients with malignant tumors using a variety of chemotherapeutic agents is sometimes rendered inadequate because of the activation of a cellular biochemical mechanism that results in resistance to drugs to which the tumor had previously been sensitive. Noninvasive imaging techniques have been developed that can identify this source of resistance to chemotherapeutic agents. Resistance of tumor cells to several structurally unrelated classes of natural products and drugs, including anthracyclines, taxanes, and epipodophyllotoxins, is often referred as multidrug resistance (MDR).1
In tumor cell lines, MDR is associated with an ATP-dependent decrease in cellular drug accumulation attributable to overexpression of ATP-binding cassette (ABC) transporter proteins. ABC transporters belong to the largest transporter gene family and generally use energy derived from ATP hydrolysis for translocation of different substrates across biologic membranes. ABC transporters are classified into seven subfamilies based on phylogenetic analysis and designated as ABCA to ABCG.2 ABC proteins that confer drug resistance include P-glycoprotein (P-gp) (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and breast cancer resistance protein (BCRP, gene symbol ABCG2).
In addition to their role in drug resistance, there is compelling evidence that in tissue defense, these efflux pumps have overlapping physiologic functions. Collectively, they are capable of transporting a large and chemically diverse range of toxins, including bulky lipophilic cationic, anionic, and neutrally charged molecules and many drugs in routine clinical use, as well as conjugated organic anions, that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products.3
Single-nucleotide polymorphisms (SNPs) in ABC drug efflux pumps may play a role in response to drug therapy and disease susceptibility. The effects of various genotypes and haplotypes (combinations of SNPs) on the expression and function of these proteins are not yet entirely clear.4 The ABCB1 multidrug resistance gene 1 (mdr1) encodes P-gp, a 170-kDa plasma membrane protein that serves as an energy-dependent adenosine-5′-triphosphate (ATP) efflux pump.5 It has been termed a molecular “hydrophobic vacuum cleaner” because it extracts substrates from the membrane and expels them to promote MDR.5,6
By protecting tissues from toxic xenobiotics and endogenous metabolites, P-gp fulfils an important physiologic role. It also regulates the transport of various structurally unrelated substrates, such as anticancer agents and toxins.7Many tissues express P-gp physiologically (Fig. 34.1),8,9 including the bronchopulmonary epithelium, hepatobiliary epithelium, renal tubular epithelium, GI tract, blood–brain barrier, and choroid plexus. P-gp in the apical border of fetus-derived epithelial cells faces the maternal circulation and is therefore optimally placed to protect the fetus against toxins.10 These tissues share the common property of a strategic location where they protect against the passage of xenobiotics. The differential expression of P-gp in many tissues, including cells of the hematopoietic system, natural killer cells, antigen-presenting dendritic cells, human peripheral blood mononuclear cells (PBMCs), and subpopulations of T and B lymphocytes, implies diverse physiologic and pharmacologic roles.10,11
FIGURE 34.1. Direction of substrate transport by P-glycoprotein (P-gp) located in various organs of the human body. The solid arrows indicate the known direction of transport, whereas the dashed arrowindicates unclear direction of transport. P-gp is located in the lipid bilayer (thick black line) that forms a barrier between various organs; red indicates vasculature, blue represents tissue, green represents tumor and white indicates excreta. CSF, cerebrospinal fluid; MDR, multidrug resistance. (Modified from Szakács G, Paterson JK, Ludwig JA, et al. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–234; Used in Kannan P, John C, Zoghbi S, et al. Imaging the function of P-glycoprotein with radiotracers: Pharmacokinetics and in vivo applications. Clin Pharmacol Ther. 2009;86(4):368–377.)
FIGURE 34.2. Genetically determined P-glycoprotein (P-gp) expression: Polymorphism in exon 26 at C3435T (silent polymorphism) influences the P-gp expression. The C/C, T/C, and T/T genotypes are associated with increased, intermediate, and low P-gp expression, respectively. High P-gp expressors (C3435C/C) are linked to MDR. Low P-gp expressors (C3435T/T) are prone to drug toxicity. SNP, single-nucleotide polymorphism.
A ROLE OF MDR1 AS A MODULATOR OF HEALTH AND DISEASE: GENETICALLY DETERMINED DIFFERENCES IN P-GLYCOPROTEIN EXPRESSION
The inter-individual variability of P-gp expression is linked to C3435T polymorphism of the human mdr1 gene which is located on the long arm of seventh chromosome at q21.1 band position. It plays a significant role in ADME processes (absorption, distribution, metabolism, and excretion) and drug–drug interactions. Variations in the mdr1 gene product can directly affect therapeutic effectiveness, with overexpression of P-gp resulting in increased efflux of anticancer drugs and development of drug resistance. The mdr1 gene is highly polymorphic and numerous SNPs have been identified, some of which influence MDR1 expression levels.7 Polymorphism in exon 26 at C3435T (silent polymorphism) also influences the P-gp expression. The C/C, T/C, and T/T genotypes are associated with increased, intermediate, and low P-gp expression, respectively (Fig. 34.2).7,12
In the analysis of MDR1 variant genotype distribution in a large sample of Caucasian subjects, Cascorbi et al.13 demonstrated that C3435T occurred in 53.9% of subjects heterozygously (T/C), whereas 28.6% of individuals were homozygous (T/T) carriers and 17.5% of the individuals were homozygous (C/C) carriers. In general, the prevalence of the T/T genotype in Caucasian individuals has been shown to be between 24% and 29%.12,13
T/T Genotype: Link with Drug Toxicity and Susceptibility to P-Glycoprotein–Mediated Disease
C3435T/T polymorphism is associated with low P-gp expression, and hence lower protection against specific P-gp–dependent xenobiotics and carcinogens and with a reduced efficiency to eliminate toxins. This results in higher intracellular concentrations of mutagens or toxins and thereby leads to DNA damage and accumulation of mutations. This reduced capacity of detoxification may have implications for disease risk and therapeutic outcomes arising from the development of drug toxicity. Thus, T/T individuals were found to be at increased risk of chronic myeloid leukemia (CML),7 acute childhood lymphoblastic leukemia (ALL),14 renal epithelial tumors,15 colorectal cancer, glioblastoma, breast cancer,7 and inflammatory bowel disease.12
With respect to gender, the T/T genotype is more frequent in males. Tumor development in response to exposure to carcinogens was found to be higher in males compared to females. The association with gender is illustrated by male glioblastoma in relation to T/T genotype as well as a greater risk of developing CML in males.7
C/C Genotype: Link with Multidrug Resistance and Poor-Risk Prognosis
Increased C/C genotype is associated with MDR and therefore with poor disease prognosis. In cancer therapy, a high expression of MDR1 makes cancer cells refractory to treatment with agents that are P-gp substrates.
The functional significance of MDR1 C3435T polymorphism with respect to imatinib treatment was studied in terms of hematologic and cytogenetic response. The frequency of the C/C genotype was significantly increased in poor cytogenetic responders to an extent that was inversely proportional to the degree of cytogenetic response. As a result of MDR, the C/C genotype is also associated with poor prognosis in ALL and AML.7,14
The effects of ABCB1 polymorphism on the handling of drugs that are P-gp substrates have also been shown to vary among races.16 Racial variability within C3434T has been demonstrated. Thus, there is a significantly higher frequency of the C/C genotype in West Africans and African Americans (83% and 61%, respectively17), compared to Caucasians (17.5%12 to 26%; p < 0.000117). This could affect treatment with drugs that are P-gp substrates (such as HIV-1 protease inhibitors and ciclosporine) and anticancer drugs in African populations17 in whom there is a higher prevalence of the relevant diseases. The development of MDR not only reflects multiple genetic and epigenetic changes in cells under cytotoxic conditions, but is also a normal physiologic response displayed by cells in their struggle to survive. The challenge of translating the concept of MDR modulation in vivo involves a complex cellular interplay between both malignant and normal cells.18
IN VIVO IMAGING OF ABC TRANSPORTERS IN MULTIDRUG RESISTANCE
MDR and specific ABC transporters may be imaged with radiopharmaceuticals that are MDR substrates or inhibitors. The most studied of these, and the first to be used, is 99mTc-sestamibi (hexakis-methoxy-isobutyl isonitrile; MIBI), which is a substrate for P-gp, MRP1, MRP2, and BCRP and can therefore be used to image their expression in vivo.19 99mTc-tetrofosmin and several other 99mTc-Q complexes that are closely related to MIBI with respect to their clinical applications are also transport substrates for P-gp and MRP.1 Although tetrofosmin and MIBI do not have identical physiologic properties, the available data suggest that the clinical imaging and in vivo modulation of MDR function can be performed with either tetrofosmin or MIBI.20 Recent studies using the positron emitter, 94Tc-MIBI and parallel previous studies with 99mTc-MIBI show essentially identical performance, thereby providing validation for micro-positron emission tomography (micro-PET).21
Several 11C-labeled P-gp–avid radioligands developed for PET, including 11C-colchicine, 11C-verapamil, 11C-daunorubicin, 11C-paclitaxel, and 11C-loperamide, have been evaluated in animals, but only 11C-verapamil and 11C-loperamide22 have been extended to humans to investigate MDR and quantify P-gp expression in the blood–brain barrier (Fig. 34.3).8,22 Other compounds that have been developed include (67/68Ga-[3-ethoxy-ENBDMPI])(+) tracers (Fig. 34.4),23 4-18F-fluoropaclitaxel,24 and the positron-labeled P-gp inhibitor, 11C-tariquidar.25
FIGURE 34.3. T1-weighted MR image (A) from representative subject and corresponding T2-weighted MR image (B) provide anatomic reference. C:11C-verapamil uptake image (SUV) before CsA treatment was acquired between 5 and 25 minutes after injection. D:11C-verapamil uptake image after 1 hour of CsA infusion shows general increase in verapamil uptake in all areas of brain after inhibition of P-gp by CsA. Color scale reflects SUV as shown by thermometer. (Reprinted with permission from the Society of Nuclear Medicine from Muzi M, Mankoff D, Link J, et al. Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-Verapamil in the brain: Studies of healthy humans. J Nucl Med. 2009;50:1267–1275. Figure 5.)
Although many studies are currently focusing on functional imaging of P-gp, other ABC drug transporters have also attracted interest. Thus, 99mTc-HIDA is transported only by MRP1, 2. Hepatic P-gp and MRP1, 2 could therefore be assessed by sequential use of both MIBI and HIDA. Leukotrienes are substrates for MRP, so N-11C-acetyl-leukotriene E4 could possibly be used to noninvasively image MRP function.1
The above imaging techniques, tracers, and their relation to relevant ABC substrates and genotypes are summarized in Table 34.1.
FIGURE 34.4. Micro-PET image of 68Ga-complex 1b in brains of FVB WT and mdr1a/1b (_/_) mice. After injection of mice with an intravenous bolus of radiopharmaceutical, images of abdomen, thorax, and head were obtained with micro-PET scanner. Representative coronal images of WT (left) and mdr1a/1b (_/_) (right) mice obtained 5 minutes after injection are shown. A body outline is included for orientation. (Reprinted with permission from the Society of Nuclear Medicine from Sharma V, Prior J, Belinsky M, et al. Characterization of a 67Ga/68Ga radiopharmaceutical for SPECT and PET of MDR1 P-glycoprotein transport activity in vivo: Validation in multidrug-resistant tumors and at the blood–brain barrier. J Nucl Med. 2005;46:354–364. Figure 7.)
99mTechnetium-Sestamibi (MIBI) as an In Vivo Assay of ABC Transporters
99mTechnetium-MIBI is a lipophilic cationic radiotracer originally introduced for imaging myocardial perfusion. Chemical analysis reveals a stable monovalent cation with a central Tc(I) core surrounded by six identical MIBI ligands, coordinated through the isonitrile carbons in an octahedral geometry.6
99mTc-MIBI is taken up by passive diffusion into cytoplasm and accumulates in mitochondria. Following intravenous injection, the tissue uptake is broadly dependent on tissue blood flow and cellularity. Cellular transport of 99mTc-MIBI is affected by apoptosis, cell proliferation, and angiogenesis. 99mTc-MIBI is therefore used to image cellular metabolism in tumors.26,27 Tissue retention is variable and markedly influenced by tissue expression of P-gp.6,28,29 The mechanism of MIBI cellular uptake is clearly different from the mechanism of elimination, which specifically reflects activity of drug transporters, such as P-gp.
MIBI has been validated as a transport substrate for P-gp in cultured MDR rodent29,30 and human tumor cells,31,6 as well as in cells overexpressing the recombinant human mdr1 gene.32 Piwnica-Worms et al.6 first demonstrated that 99mTc-MIBI is a substrate of P-gp and that it can be used as a functional imaging agent for P-gp in tumor xenografts in nude mice. They and others have shown that tumor retention of 99mTc-MIBI correlates inversely with the degree of P-gp expression and can be modified in vitro by P-gp antagonists.33
In rodent models, tumors that express P-gp eliminate 99mTc-MIBI faster than those that do not.29,31 The hepatic and renal excretion pathways of 99mTc-MIBI are mediated by P-gp and can be modulated in humans following administration of cytotoxic drugs. Thus, intravenous administration of a P-gp modulator delayed excretion of MIBI from the liver and kidney in patients investigated for MDR.34 In vitro MIBI studies have shown that P-gp inhibitors, such as verapamil and ciclosporin, can reverse P-gp expression in adenocarcinoma cells if given shortly before the administration of a cytotoxic drug.35
Additional mechanisms of cell resistance, mainly involving alterations of apoptosis, may also affect 99mTc-MIBI uptake in tumors. In particular, overexpression of the antiapoptotic protein, Bcl-2, prevents tumor cells entering apoptosis and inhibits 99mTc-MIBI accumulation in mitochondria. So, although absent or reduced early tracer uptake in breast carcinomas reflects the existence of a defective apoptotic program, an enhanced tracer clearance in 99mTc-MIBI–positive lesions reflects the activity of drug transporters, such as P-gp. The existence of two different mechanisms underlying the predictive role of 99mTc-MIBI scan may be important to establish whether individual patients may benefit from P-gp inhibitors or Bcl-2 antagonists.36
SPECT AND PET ABC SUBSTRATES (S) AND INHIBITORS (I) AND THEIR RELATIONSHIPS TO GENES
It has been demonstrated that preoperative washout rates of 99mTc-MIBI from primary breast tumors correlated with levels of P-gp semiquantified by immunohistochemistry in the surgically resected specimens (Fig. 34.5).
Imaging in patients with breast cancer demonstrated that 99mTc-MIBI washout rates from cancers overexpressing P-gp are threefold faster than those from cancers not expressing P-gp.37,38
99mTc-MIBI has also been used to image MDR in lung cancer,39 brain tumors,40,41 gastric cancer,42 head and neck cancer,43 hepatobiliary cancer,44 and hematologic malignancies.45
In lung cancer, the sensitivity, specificity, and accuracy of 99mTc-MIBI to identify responders to chemotherapy are 94%, 90%, and 92%, respectively.39 There is evolving evidence that 99mTc-MIBI is cost-effective in predicting the response to chemotherapy in patients with lung cancer39 and also for diagnosing breast cancer in patients with indeterminate mammography and dense breasts.46
FIGURE 34.5. Images of breast cancer obtained 20 minutes (early) and 120 minutes (late) after injection of 99mTc-MIBI. A: A patient with tumor displaying immunohistochemically negative P-gp expression showing tumor/background (T/B) that increased from 1.65 to 1.99 between early and late images. B: A patient with tumor displaying strongly positive P-gp expression showing T/B that decreased from 2.25 to 1.52 between early and late images. (Reprinted with permission from the Society of Nuclear Medicine from Mubashar M, Harrington KJ, Chaudhary KS, et al. 99mTc-Sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer. J Nucl Med. 2002;43(4):519–525.)
In thyroid imaging, 99mTc-MIBI scintigraphy can be used to reliably exclude thyroid cancer when ultrasound-guided fine-needle aspiration cytology (US-FNAC) is nondiagnostic thus avoiding more invasive surgery and costs.47 It has, however, only recently been demonstrated that semiquantitative 99mTc-MIBI scintigraphy may preoperatively predict the malignant behavior of nononcocytic follicular thyroid nodules indeterminate at fine-needle aspiration biopsy. Moreover, a good correlation was found between immunohistochemical apical expression of MRP1 and 99mTc-MIBI scintigraphy. A negative MIBI retention index correlated strongly with those cases with high MRP1 expression. 99mTc-MIBI scintigraphy, therefore may provide information on the molecular expression of MRP1 in thyroid.48
A potential role for 99mTc-MIBI scintigraphy has been investigated in the management of hematologic malignancies, particularly multiple myeloma (MM), in which it has been shown that the rate of MIBI elimination can predict response to chemotherapy. Patients showing disease progression at restaging had higher elimination rates (19.3 ± 9.8% versus 12.8 ± 6.9%, p < 0.05) than patients in remission. Disease-free survival was significantly longer in patients with lower elimination rates. When patients treated with melphalan were excluded from the analysis, 87.5% of patients in remission had slow elimination.49
In general and in relation to a range of malignancies, patients whose tumors showed MIBI uptake responded well to chemotherapy, whereas those whose tumors showed little or no uptake or a rapid rate of MIBI washout did not respond well.8
Genetically determined responses to some anticancer drugs may also influence anticancer treatment. It has been shown that imaging the liver with 99mTc-MIBI may provide pretreatment indicators of ABCB1-mediated hepatic drug clearance in cancer patients. MIBI hepatic elimination (kH) was significantly reduced in patients with SNPs in exons 21 and 26. The mean MIBI kH was respectively 1.90 times and 2.21 times higher in subjects homozygous for the wild-type alleles compared to those homozygous for these SNPs.50
History of ABC Drug Transporters and Imaging
Based on the premise that blockade of ATP-dependent drug efflux pumps will enhance the effect of chemotherapy, there has been an intense search for compounds able to reverse MDR in cultured cells, animal models, and patients. There have been many attempts to image these pumps using both single photon emission tomography (SPECT) and PET tracers.39 However, administration of P-gp or MRP1 modulators has failed to show any significant clinical benefit in patient outcome, mainly because of toxicity (first generation) or interaction with anticancer drugs and alteration in pharmacokinetics of the chemotherapy agents (second generation). These MDR tracers have not, therefore, found routine clinical use.
Promising clinical trials have been conducted in acute myeloid leukemia, breast cancer, and non-Hodgkin lymphoma, all of which are known to express P-gp. Paradoxically, several studies focused on MDR reversal in cancers in which resistance may not be P-gp mediated. Several clinical trials, including the phase III trials of tariquidar, not surprisingly yielded negative results in cancers in which P-gp expression is generally low, such as small-cell lung cancer and non–small-cell lung cancer.8 Poor study design, regarding either dosing regimens or patient selection, and genetic polymorphism of P-gp were further major reasons for negative results in clinical trials using third-generation P-gp modulators. The two major phase III trials of tariquidar in patients with non–small-cell lung cancer were terminated prematurely because of toxicity as a result of higher doses of chemotherapy than recommended. Furthermore, the prevalence of various genetic polymorphisms of P-gp may have influenced results (both negatively and positively). Some SNPs and haplotypes of the mdr1 gene have been shown to alter P-gp expression and activity both in vitro and in vivo. For example, patients with ovarian cancer who express the wild-type allele for P-gp had a mean progression-free survival of 19 months when treated with chemotherapy, whereas in those expressing the G1199A polymorphism, corresponding survival was only 2 months.8 Other studies have shown a relation with C3435T polymorphism. All the factors mentioned above may influence imaging outcome in an individual patient, leading to controversial results, and so functional imaging of MDR remains under-utilized in clinical practice.
Clinical trials better tailored to tumor types, genetic polymorphism, and adequate dosing regimens need to be conducted because imaging may be useful for selecting patients whose cancers express MDR primarily through ABC-mediated mechanisms. For a proper assessment of P-gp levels in tumors, patients should undergo two scans with a P-gp radioligand: At baseline and again after P-gp inhibition. Patients whose tumors show enhanced uptake of the radioligand following P-gp blockade would be suitable candidates for P-gp inhibitor trials (Fig. 34.6).8,51
FIGURE 34.6. 99mTc-sestamibi images at baseline and after administration of XR95767 for patients 3, 5, and 10. Patient numbers are shown in parentheses. A: Arrow identifies a left thigh mass that had gone undetected until the whole-body 99mTc-sestamibi scan was performed (patient 3, renal cell carcinoma, 263% increase in tumor: Heart AUC 0- to 3-hour ratio). B: Arrow indicates a soft tissue mass invading the iliac bone (patient 5, renal cell carcinoma, 18% increase in tumor: Heart AUC 0- to 3-hour ratio). C: Arrows indicate numerous bilateral lung metastases that are all more readily visualized after the administration of XR9576 (patient 10, adrenocortical carcinoma, 76% to 191% increase in tumor: Heart AUC 0- to 3-hour ratios. (Reprinted with permission from the American Association for Cancer Research: Agrawal M, Abraham J, Balis FM, et al. Increased 99mTc-Sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clin Cancer Res. 2003;9:650–656.)
Two studies using 99mTc-sestamibi following administration of tariquidar or valspodar have shown the utility of this approach. Another ongoing study is using MIBI to monitor progress throughout the trial.8
Prolonged exposure of cells to P-gp inhibitors may cause physiologic upregulation of P-gp.52 As many inhibitors are also modulators, initial downregulation may be followed by upregulation, resulting in acquired drug resistance to P-gp inhibitors. Functional imaging may be used to monitor physiologic prolonged P-gp response to P-gp inhibitors, in addition to an acute response.
Ongoing research has led to the development of a third generation of MDR modulators, some of which have demonstrated encouraging results compared with earlier modulators. They are less toxic, more P-gp specific, and do not affect the pharmacokinetics of anticancer drugs. Some MDR-reversing strategies aim to destroy mRNAs for ABC drug transporters, inhibit transcription of ABC transporter genes, or block ABC transporter activity using monoclonal antibodies. There is an optimistic view that much more can be achieved in developing agents for reversing ABC transporters.53 It is therefore likely that with the development of more potent P-gp inhibitors, effective imaging agents that are analogs of ABC transporters will emerge.
In the post-genomic era of individualized medicine, ABC imaging may be helpful to adjust the treatment dose in individual patients. More research is needed to identify patients, through imaging, who are susceptible to drug toxicity side effects, to provide information concerning dose adjustment, and to allow better decision making when considering therapy with anticancer drugs that are ABC transporter substrates.
It has emerged that combinations of chemotherapeutic drugs involved in MDR with the so-called targeted agents may improve patient outcome. Molecular imaging can be used to visualize the targets for these agents, such as HER2/neu and angiogenic factors such as vascular endothelial growth factor (VEGF). Visualization of molecular drug targets in the tumor could function as biomarkers to support treatment decisions for the individual patient.1Simultaneous combined imaging using both MDR and target analogs may also evolve initially in the clinical trials setting and this potential role is yet to be explored.
Functional imaging of MDR in cancer may be helpful not only in the detection of drug-resistant tumors, but also in the identification of patients who are susceptible to the development of certain malignancies or drug toxicities. SNPs for the mdr1 gene may be associated with altered oral bioavailability of drugs given orally, with drug resistance, and with susceptibility to some human diseases. As an ABC transporter substrate, 99mTc-MIBI is a noninvasive, cost-effective imaging agent for identifying MDR in tumors but, although readily available, is underutilized in clinical practice. Molecular functional imaging may guide individual treatment doses, thereby decreasing drug toxicity or avoiding ineffective treatment in drug-resistant tumors while at the same time reducing the costs of potentially ineffective therapy.
Primary intrinsic and/or acquired MDR is the main obstacle to successful cancer treatment. Functional molecular imaging of MDR in cancer using single photon or positron emitters may be helpful to identify multidrug-resistant tumors and predict not only those patients who are resistant to treatment with a clinically unfavorable prognosis, but also those who are susceptible to the development of drug toxicity or even certain tumors. Variations in the mdr1gene product may directly affect the therapeutic effectiveness, and SNPs for the mdr1 gene may be associated with altered oral bioavailability of MDR1 substrates, drug resistance, and a susceptibility to some human diseases. The challenge of translating the concept of MDR modulation in vivo involves a complex cellular interplay between both malignant and normal cells. Integration and correlation of functional SPECT or PET imaging findings with mdr1genotype and clinical data may contribute to efficient management by selecting cancer patients with the appropriate molecular phenotype for maximal individual therapeutic benefit, as well as those who are nonresponders. A role for functional imaging of classical mechanisms of MDR with an emphasis on readily available 99mTc-MIBI scintigraphy has been described. MIBI scintigraphy has been shown to be a noninvasive cost-effective in vivo assay of ABC transporters associated with MDR in cancer, including P-gp, multidrug-resistant protein 1 (MRP1) and breast cancer resistance protein (BCRP). Functional imaging can investigate a relationship between genetic polymorphisms of P-gp and its function in vivo. Individualized treatment could be provided to cancer patients because MDR levels in tumors could be determined before or during chemotherapy treatment by radionuclide imaging of ABC protein transporters.
New imaging agents for molecular targets such as VEGF and HER2 receptors may potentially be combined with MDR imaging substrates to more accurately predict the therapeutic response to anticancer drugs, guiding individualized treatment while minimizing the health economic cost of ineffective therapy in an era of personalized medicine.
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