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Oncological molecular imaging: nuclear medicine techniques

Department of Nuclear Medicine & PET, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK

	Introduction

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
With the expanding interest and development in molecular biology, nuclear medicine imaging, essentially a molecular imaging technique studying biological processes at the cellular and molecular level, has much to offer. As other non-isotope techniques develop there has also been an opportunity for nuclear medicine to broaden its horizons in this field. Nuclear medicine's involvement in molecular imaging has been enhanced by the improvement in single photon emission computed tomography (SPECT), the wider availability of positron emission tomography (PET) and a greater input and new developments in radiochemistry.

Nuclear medicine can be regarded as a method by which biological processes may be non-invasively monitored by radiopharmaceuticals delivered in tracer amounts. By measuring radioactive concentrations in tissue samples, either directly or by means of imaging, it is possible to explore and quantify biological processes in health and disease at the molecular or cellular level.

The major advantage of nuclear medicine methods is that only picomolar concentrations of radiotracers are required to provide a measurable signal without interfering with the process under investigation. It is often true that biochemical or metabolic changes can therefore be identified before a significant change in structure or anatomy can be determined. In oncology this has the potential advantage of not only being able to detect abnormal function related to malignant tissue at diagnosis but also to identify changes as a result of therapy earlier than is possible with anatomical techniques alone. However, this high sensitivity is often at the expense of inferior spatial resolution. Here PET techniques show advantages over SPECT, as not only is spatial resolution better, but positron emitting radionuclides include isotopes of carbon (¹¹C), nitrogen (¹³N) and oxygen (¹⁵O), allowing radiolabelling of biological compounds of interest. SPECT relies more frequently on the use of radiolabelled analogues. The spatial resolution of PET remains inferior to that of anatomical techniques including CT, MRI and ultrasound but with the advent of combined dual-modality scanners, such as PET/CT, it is possible that some of the disadvantages of the two techniques may be minimized and the advantages maximized.

Another potential disadvantage of SPECT and PET techniques is that the measured signal is not chemically specific; for example, it is not possible to differentiate signal between the administered radiopharmaceutical and its metabolites without more complex metabolite analysis in blood.

Due to the spatial resolution advantages of PET over SPECT, coupled with an ability to more accurately correct for attenuation of photons, quantitative accuracy is superior with PET. Absolute measurements of radioactive concentrations in tissue over time allow the measurement of dynamic processes in absolute units such as ml min^–1 ml^–1.

Realistic goals of nuclear medicine in oncological molecular imaging are to develop high affinity, high specific activity radiopharmaceuticals, allowing quantitation of molecular processes in whole tumour in a reproducible and repeatable manner.

In oncology there are a number of areas where nuclear medicine techniques may give information on molecular and cellular events, many of which are already absorbed into routine clinical practice and others that are at a more developmental stage. These applications include the detection and measurement of a number of events in untreated tumours, including glycolysis, proliferation, membrane synthesis and receptor expression, amongst many others. In treated tumours there are methods to non-specifically measure the downstream effect of cytotoxic therapies but with the development of molecular therapies targeting specific aspects of cancer cell biology there is a greater interest in the development of markers aimed at specifically measuring the molecular consequence of each therapeutic agent. For example, a marker to measure the amount of tumour angiogenesis is likely to be a more sensitive measure of response to an antiangiogenic agent than a non-specific marker of downstream effects such as tumour cell viability.

Molecular imaging techniques may also allow us to tailor therapy to individual patients. Visualization of specific molecular targets prior to therapy may identify patients most likely to benefit from a particular molecular therapy. Many novel anticancer therapies are cytostatic rather than cytotoxic and conventional methods of measuring treatment response may be particularly insensitive when tumour shrinkage is not anticipated but where functional changes may be marked. It is here that nuclear medicine techniques also have a role to play and it is important that molecular imaging techniques are developed in conjunction with molecular therapeutics for some of the reasons stated above. Additionally, in nuclear medicine there is the opportunity to label specific molecular probes with or emitting radionuclides to deliver a therapeutic dose of targeted radiation to abnormal cells that concentrate these radiopharmaceuticals whilst minimizing radiation dose to normal tissues.

Tumour glycolysis
Perhaps one of the most successful molecular imaging techniques to be rapidly incorporated into routine clinical management in oncology is ¹⁸F-fluorodeoxyglucose (¹⁸FDG) PET. It has been known for many years that malignant tissue is associated with an increased utilization of glucose [1]. Many cancers are known to overexpress glucose transporters, including Glut-1, that allow entry of glucose and the radiolabelled analogue, ¹⁸FDG [2]. Both glucose and DG are then phosphorylated by hexokinase with glucose entering the tricarboxylic acid cycle but DG remaining effectively trapped due to a high negative charge and no entry into significant further enzymatic reactions. As there is low activity of glucose-6-phosphatase in most malignant and normal tissues there is relatively little dephosphorylation of ¹⁸FDG and therefore accumulation is proportional to glycolytic rate. ¹⁸FDG-PET is therefore a method for measurement of the molecular and cellular events involved in glycolysis. As these processes are enhanced in malignant tissue there is preferential accumulation of ¹⁸FDG compared with normal tissue, that with modern PET scanning systems can be detected with high sensitivity and where the signal from active tumours as small as a few millimetres can be identified. There is now incontrovertible evidence that ¹⁸FDG-PET has incremental value over standard imaging techniques, significantly altering patient management in many cancers [3] but especially in the staging of lung cancer, recurrent colorectal cancer and lymphoma.

¹⁸FDG-PET scanning is commonly performed at 1 h after injection as a compromise between patient convenience, half-life of ¹⁸F (110 min) and tumour uptake. There are benign processes that may show enhanced uptake of this radiopharmaceutical that may be potentially mistaken for malignancy. However, it has been noted that malignant cells continue to accumulate ¹⁸FDG for a number of hours [4] and either scanning at 4 h or dual time-point scanning, e.g. at 1 h and 2 h, [5] may lead to better discrimination between benign and malignant processes. In the latter method, malignant cells continue to accumulate ¹⁸FDG between 1 h and 2 h whilst benign tissue does not.

Although semiquantitative measurements of uptake on static scans at 1 h are convenient and relatively simple for clinical use, a more thorough knowledge of the kinetics of ¹⁸FDG metabolism can be acquired by dynamic scanning and measurement of arterial blood activity over time. Although not practical in the routine clinical setting, this method may allow calculation of various rate constants with a more detailed and possibly, more discriminating measure of malignant cell biology [6]. Most commonly, a non-linear regression method is used to calculate the various rate constants describing ¹⁸FDG kinetics by using dynamic tissue data from the PET scan, dynamic arterial data, either directly from arterial measurement or indirectly from arterial image data, and a three compartment model consisting of blood ¹⁸FDG, free ¹⁸FDG in the tissue and phosphorylated ¹⁸FDG (Figure 1).

View larger version (8K): [in this window] [in a new window]   Figure 1. A three compartment model of cellular fluorodeoxyglucose (FDG) trapping.

Although a marker of glycolysis, uptake of ¹⁸FDG has been correlated with a number of processes and states including tissue viability, cellular proliferation, tumour hypoxia and inflammatory cell infiltrate associated with tumours [7–9].

Currently ¹⁸FDG PET is used predominantly as a sensitive clinical staging technique but the promise and interest for the future is to use it as an indirect marker of therapy response giving information on residual tumour cell viability, either early in a course of therapy to assess efficacy of a treatment regimen or at the end of therapy to differentiate tumour from fibrosis in residual masses. In the former there is some evidence that changes in uptake of ¹⁸FDG pre-date changes in tumour size and it may therefore be possible to assess efficacy of chemotherapy after one or two cycles, with the option to change treatment and avoid further potential toxicity in those not responding [10]. In fact, significant changes in ¹⁸FDG uptake have been seen as soon as 1 day after starting therapy in patients with gastrointestinal stromal tumours responding to imantinib mesylate [11]. In the latter, the more accurate prediction of residual viable tumour will help avoid long-term toxicity from radiotherapy in patients who are PET-negative.

In the hope that uptake of ¹⁸FDG reflects extent of viable tumour better than conventional anatomical imaging techniques, there is great interest in using ¹⁸FDG PET in radiotherapy planning. Interest has accelerated since the introduction of combined PET/CT systems whereby the accurately co-registered CT scan can provide anatomical reference for the functional map of ¹⁸FDG uptake, allowing a maximization of dose to tumour tissue whilst minimizing toxicity to surrounding non-tumour tissues [12].

	Tumour proliferation

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
Whilst it is possible to see changes in tumour uptake of ¹⁸FDG soon after initiating therapy, it is known that some of the signal is due to uptake into activated inflammatory cells after chemotherapy but particularly after radiotherapy, in some situations. As mentioned above, the change in signal may not specifically reflect the mode of action of the anticancer agent being used. For these reasons there has been interest in developing pyrimidine analogues to monitor DNA activity and tumour proliferation more directly. Whilst ³H and ¹⁴C labelled thymidine have been validated as lab techniques for measurement of proliferation in tissue samples, initial in vivo imaging studies used ¹¹C labelled thymidine. However, use of this positron-emitting radiopharmaceutical is hampered by the short 20 min half-life of ¹¹C-carbon and its breakdown to a number of metabolites. ¹⁸F-fluorothymidine (¹⁸FLT) is a more attractive radiopharmaceutical as it resists degradation and has a more convenient half-life [13]. In a similar model to ¹⁸FDG accumulation, ¹⁸FLT is trapped intracellularly following phosphorylation by thymidine kinase 1 (TK1). Although this does not reflect the full incorporation of thymidine into DNA, uptake of ¹⁸FLT has been shown to correlate with other markers of cellular proliferation including Ki-67 [14]. In cell cultures there is evidence of a correlation between ¹⁸FLT uptake and TK1 activity as well as the fraction of cells in S phase [15]. It is early days in the evaluation of this tracer and as yet it is unknown whether it will live up to the hopes of tumour specificity and treatment effect sensitivity.

It is possible that changes in tumour uptake of ¹⁸FLT will depend on the type of cytotoxic therapy being used. For example, some agents may lead to an initial increase in uptake of ¹⁸FLT that reflects activation of the salvage pathway of DNA synthesis rather than changes in proliferation [16] and so more knowledge of the use of this tracer is specific situations must be acquired before its more routine use.

	Tumour hypoxia

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
The importance of tumour hypoxia is that its existence may confer resistance to some tumours during radiotherapy and some forms of chemotherapy and may be associated with poorer prognosis [17]. As tumour hypoxia cannot be predicted, either direct or indirect measurements of hypoxia are required to identify patients who may benefit from more aggressive therapy. Examples of such treatments include the administration of hypoxia sensitizers [18], hyperbaric oxygen therapy [19] or boosting radiation doses to hypoxic tissue with intensity-modulated radiotherapy (IMRT) [20] techniques. It remains very difficult to predict tumour hypoxia in individual patients as there is both intertumoural and intratumoural variation in oxygen status and no consistent relationship between oxygen status and hypoxic fraction and tumour size [21]. Nuclear medicine offers non-invasive methods for demonstrating tissue hypoxia, the gold standard requiring transdermal electrode measurements that are invasive, prone to sampling errors and not practical for clinical routine.

Compounds that are selectively trapped in hypoxic tissue may be labelled with positron-emitting radionuclides or single photon gamma emitters, including technetium-99m (⁹⁹Tc^m). The nitroimidazole-containing compounds have received most attention with a number of compounds containing a 2-nitroimidazole moiety as a bioreductive molecule. The nitro group undergoes one electron reduction in viable cells to produce a radical anion. In hypoxic cells this intermediate is further reduced to species that react with cellular components and remain trapped within the cell. In normoxic cells rapid re-oxidation takes place allowing the compound to diffuse out of the cell.

Fluorine-18 labelled fluoromisonidazole (¹⁸F-miso) is probably the most extensively studied hypoxia-selective radiopharmaceutical using PET. A number of malignant tumours including squamous cell carcinomas of the head and neck [22] and non-small cell lung cancer [23] have been studied with this compound. As the majority of tumours studied in these series exhibited some degree of hypoxia and because the degree of hypoxia varied greatly, quantification of fractional hypoxic volume [21] or more complex mathematical modelling [24] may be important to accurately identify those patients who should be offered more aggressive therapy.

In the SPECT world there has also been interest in labelling nitroimidazole compounds, initially directly with iodine isotopes or via iodinated sugars [25]. More recently there have been reports of successful imaging with ⁹⁹Tc^m of nitroimadazoles and some of their core ligands [26, 27].

In spite of a number of promising PET and SPECT radiopharmaceuticals having been described for hypoxia-selective imaging, further work is required to correlate uptake with the degree of tissue hypoxia, or perhaps more importantly, with tumour resistance to therapy. Once these important steps are made it will be possible to design trials where tumour hypoxia identified by non-invasive nuclear medicine techniques can be used to select patients for new therapies designed to overcome hypoxia induced resistance.

	Tumour angiogenesis

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
In malignant tumours the process of neoangiogenesis results in the formation of a chaotic network of a complex capillary growth stimulated by agonists including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), integrins and others. Without angiogenesis, tumour growth is limited to 1–2 mm and one of the other reasons that tumour angiogenesis has been a therapeutic target is that it is associated with metastatic potential and implantation of tumours. With the intense interest in producing angiogenesis inhibitors as anticancer agents there is a need for markers to directly monitor the effects of these drugs. As many are cytostatic, rather than cytotoxic, measurement of changes in tumour size may not be the most sensitive means of response evaluation and there is a need for functional methods. In addition, the identification of particular molecular markers of angiogenesis in an individual tumour may allow the selection of patients who are most likely to benefit from a particular antiangiogenic treatment. As angiogenesis is related to factors such as metastatic potential it is possible that angiogenic molecular imaging may also be used as a prognostic marker. A potential advantage of targeting molecular processes related to angiogenesis, rather than those related to the tumour cells themselves, is that the vascular angiogenic targets are potentially more accessible, allowing rapid imaging with high target signal. The other potential advantage of targeting molecular processes involved in tumour angiogenesis is that therapeutic radiopharmaceuticals can be directed at the same targets. This may not only inhibit the angiogenic process, and therefore tumour growth directly, but also impart a therapeutic dose of radiation to tumour cells from the bystander effect.

A number of methods have been described to image and quantify the angiogenic process, using direct or indirect measurements with both PET and SPECT radiopharmaceuticals. The simplest of these is to measure tumour perfusion, commonly with tracers with high or predictable first pass extraction. For example, the uptake of ⁹⁹Tc^m sestamibi into a mouse breast cancer model has been correlated with tumour microvessel density (MVD) [28]. Results in human breast cancers have been variable [29, 30] and further work on the methodology and timing of imaging this compound is required. This compound is lipophilic and its uptake is associated with mitochondrial activity but the mechanisms of uptake with relation to correlations with tumour perfusion and vessel density are not fully understood. Another lipophilic perfusion SPECT agent, ⁹⁹Tc^m hexamethyl-propylene amine oxime (HMPAO), has been used to determine tumour perfusion in humans, [31] and has also been used to measure changes in perfusion after pharmacological intervention [32].

The superior quantitative accuracy of PET has also led to interest in measuring tumour blood flow with this method. Pharmacologically induced changes in blood flow have been measured in colorectal liver metastases using copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (⁶²Cu-PTSM) PET and shown to be highly variable in individual patients [33]. This technique may therefore be of use in selecting patients for particular pharmacological interventions.

Similarly the pharmacodynamic response of the antivascular agent, combretastatin, has been measured with H₂¹⁵O PET in advanced solid tumours. Dose-dependent reduction in tumour perfusion could be identified as soon as 30 min after administration of combrestatin that at lower doses showed recovery at 24 h [34]. This important study revealed the potential for functional imaging methods in not only measuring tumour vascular shutdown but also in assessing the timecourse of antivascular effects.

Rather than measuring tumour blood flow directly there has also been interest in imaging specific molecular targets involved in tumour angiogenesis. Tumour derived VEGF and its associated capillary endothelial receptors are examples and there is early work in humans where gastrointestinal tumour VEGF receptors have been imaged with ¹²³I-iodine labelled VEGF [35]. Therapeutic radiopharmaceuticals including ¹³¹I-labelled anti-VEGF antibodies have also been shown to reduce tumour growth and metastatic potential in a murine spontaneous breast cancer model [36].

Integrins are transmembrane adhesion receptors involved in regulating the proliferation and survival of endothelial cells implicated in tumour angiogenesis and offer themselves as a further target for imaging with radiopharmaceuticals. These compounds, including _V3 integrin, are preferentially expressed on activated endothelial cells and tumours and recognise the arginine-glycine-aspartic acid (RGD) sequence and hence are targeted by RGD containing peptides. Glycosylated RGD containing peptides have been successfully labelled with both SPECT and PET radionuclides including iodine isotopes, ⁹⁹Tc^m and ¹⁸F [37–39].

Early work has demonstrated successful imaging of melanoma metastases with a synthetic peptide containing two RGD sequences and labelled with ⁹⁹Tc^m [40]. Six of eight metastatic lymph nodes and 75% of other metastatic lesions showed measurable uptake and therefore evidence of integrin binding on tumour cell surfaces.

	Tumour choline metabolism

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
Elevated levels of choline, phosphocholine and phosphoethanolamine have been detected in a number of cancers by MR spectroscopic and biochemical techniques, correlating with increased cellular membrane phospholipid synthesis rates. There are some limitations associated with the most commonly used clinical PET tracer, ¹⁸FDG, related to specificity and tumour detection where there is high background activity, including the brain and urinary tract. Choline tracers including ¹¹C-choline, and more recently ¹⁸F-choline, have been developed with these limitations in mind. It is hoped that uptake of these tracers will correlate with increased membrane synthesis and hence cellular proliferation.

There are early clinical data suggesting favourable imaging characteristics in many cancers, including primary brain tumours and prostate cancer that are inadequately imaged with ¹⁸FDG [41, 42].

	Tumour apoptosis

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
Programmed cell death or apoptosis is thought to be an inherent part of successful treatment of tumours with chemotherapy or radiotherapy. Once apoptosis is triggered a series of enzymatic cascades are initiated to ensure the orderly destruction of the cell and its constituents. One of the major pathways involved includes activation of caspases. As a result of this phosphatidylserine (PS), usually restricted to the inner cell membrane, is externalized. Annexin V, an endogenous human protein with a molecular weight of 36000, binds to PS with very high affinity. Annexin V has been labelled with ¹²⁴I-iodine as a PET tracer [43] and ¹²³I-iodine [44] and ⁹⁹Tc^m as SPECT tracers [45].

Accumulation of Annexin V appears to correlate with apoptosis as measured by other means [46] but it is likely that binding will also occur non-specifically during necrosis during membrane breakdown when PS is exposed. However, it is hoped that the ability to image apoptosis will allow an accurate evaluation of cytotoxic therapy effect soon after the administration of the therapeutic agent. A preliminary study of 15 patients with lung, lymphoma or breast cancer is promising [45]. No tumour-related uptake was seen at baseline but measurable uptake was identified as soon as 24–48 h after the first course of chemotherapy in seven patients who went on to have a complete (n=4) or partial (n=3) response by conventional criteria. In contrast, six of eight patients without an increase in uptake showed progressive disease.

The sensitivity of the technique for detecting low levels of apoptosis against non-specific background activity or the ability to differentiate apoptotic cell death from other mechanisms remains unknown but progress is being made with a number of refinements to the imaging method [47].

	Gene delivery and expression

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
Perhaps one of the most exciting areas of molecular imaging is that related to the expression and function of various tumour related genes and how genes are delivered and expressed during novel gene therapy techniques. The main current methods for demonstrating gene expression require tissue samples and therefore non-invasive methods to identify and quantify gene transfer and protein expression in vivo are in great demand. Gene therapy may be unsuccessful due to inefficient delivery of the gene to the target tissue, but whatever the method of gene transfer, e.g. viral vector, typically a reporter gene can be used to confirm successful transfer and expression in target cells. Common approaches have employed both enzyme and receptor-mediated gene imaging. Once validated, a reporter gene/probe system can potentially be used to interrogate any gene of interest.

The most commonly used system in PET imaging employs the herpes simplex virus 1 thymidine kinase (HSV-TK) enzyme. If viral thymidine kinase is successfully expressed in a cell it will phosphorylate nucleoside analogues (e.g. ganciclovir), which then becomes trapped in the cell. Mammalian thymidine kinase will not phosphorylate these nucleoside analogues. If nucleoside analogues can be radioactively labelled, after active transport and subsequent phosphorylation, the accumulation of radioactivity should indicate HSV-TK expression and hence successful transfection. In the absence of HSK-TK, nucleoside analogues that enter the cell will not be phosphorylated and therefore do not accumulate. A number of PET radiopharmaceuticals have been used to test for HSV-TK expression including ganciclovir, 5-iodo-2-deoxyuridine (IUDR), 5-iodo-2-fluoro-2-deoxy--D-arabinofuranosyl uracil (FIAU) [48–50] and others. This work is still largely at the animal stage but successful imaging of HSV-TK expression has been accomplished.

Receptor mediated gene expression relies on the encoding of cell surface receptors for which radiolabelled substrates are available. An example is the dopamine 2 (D2) receptor that can be delivered by a viral vector to transfect tumour cells that can then be imaged with substrates such as ¹¹C-raclopride or ¹⁸F-fluoroethylspiperone [51].

Whilst a number of models for the imaging and quantitation of gene expression are being developed in animals, it is anticipated that if successful in man, these non-invasive methods may accelerate and facilitate gene therapy techniques.

	Tumour multidrug resistance

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
Multidrug resistance (MDR) is a major factor in the failure of chemotherapy in cancer. There are a number of different mechanisms for MDR but one of the most studied involves the MDR-1 gene and its protein, P-glycoprotein (Pgp), as well as the multidrug resistance protein, MRP. These act as ATP-dependent efflux mechanisms for a number of drugs including anthracyclines, taxol, vinca-alkaloids and others. Identification and measurement of MDR is of potential importance as it may affect choice of drug in an individual patient but also because MDR modulators are being developed that inhibit MDR proteins and enhance tumour accumulation of chemotherapeutic compounds.

Sestamibi, a cationic, lipophilic compound developed for myocardial perfusion imaging, is a substrate for Pgp, and when labelled with ⁹⁹Tc^m, can be used as a marker of Pgp transport activity. Therefore resistant tumour cells will show minimal or absent uptake or enhanced washout of this compound. In human studies, efflux rate of sestamibi from breast tumours has been correlated with Pgp expression [52] and inversely correlated with therapeutic response to chemotherapy [53]. In addition, Pgp modulation with PSC 833 has been shown to be associated with increased accumulation of ⁹⁹Tc^m sestamibi in tumours and the liver in man [54].

Other single photon agents including ⁹⁹Tc^m-tetrofosmin and PET agents such as copper bis(diphosphine) complexes have been investigated as probes for imaging drug resistance [55].

	Conclusions

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 
Molecular imaging is not based on a single imaging methodology and nuclear medicine techniques are just a small part of the available tools being developed in this field. This review has concentrated on some of the more important oncological aspects of molecular imaging that are relevant to nuclear medicine that have been, or are close to being applicable to man. Many of these techniques have developed through initial animal work and microPET and microSPECT techniques also continue to progress. Of course, there are many other nuclear medicine techniques that are relevant including imaging of the sodium iodide symporter in thyroid and breast cancer, monoclonal antibody targeting of tumour antigens, imaging of other peptide ligands, amongst others.

Nuclear medicine has already contributed to molecular imaging in oncology for many years and is likely to remain one of the important tools amongst the others described in this publication as molecular biology and molecular medicine progress.

	References

Top Introduction Tumour proliferation Tumour hypoxia Tumour angiogenesis Tumour choline metabolism Tumour apoptosis Gene delivery and expression Tumour multidrug resistance Conclusions References

 

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