Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 7, Issue 3, 2007

The rapid development of clinical diagnostic imaging technology, in combination with medical and pharmaceutical research, has led to important improvements in healthcare. Imaging of biologic processes at cellular and molecular levels termed “molecular imaging” is one of the most innovative examples. In contradistinction to “conventional” diagnostic imaging, it sets forth to probe abnormalities that are the basis of diseases, rather than imaging advanced stage disease. This will be of great importance for the detection of early stages of malignant tumours. The development of highly sensitive agents will result in early tumour detection, which is expected to cause a substantial shift in healthcare procedures. Much more emphasis will be placed on diagnosing and treating disease before late symptoms occur, which demands a new category of therapy strategies. Development of innovative drugs and carrier systems is desired. Visualization of drug targeting and efficacy with high-resolution molecular imaging offers the opportunity to test and improve treatment in detail. However, not all presently used “high-end” imaging technologies can obtain molecular information. The different imaging modalities each have their own characteristics, strengths and weaknesses, which makes it beneficial to combine them. Therefore imaging techniques like single photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) are combined resulting in SPECT-CT, PET-CT and PET-MRI. This offers the opportunity to merge the image of the agent distribution with the anatomy of the patient. Further improvements of these combined imaging apparatus are currently under investigation. Most interestingly, there is an increasing interest in the development of imaging contrast agents for these new opportunities provided by the combined imaging modalities. Drug carriers such as liposomes, micro- and nanoparticles, peptides and antibodies are able to modify the distribution of an associated substance. They can therefore be used to improve the therapeutic index of drugs increasing their efficacy and/or reducing their toxicity. If these delivery systems are carefully designed with respect to the target and route of administration, they will increase the specific targeting of the tumour. In addition, if these systems could be equipped with components that can be visualized with dedicated imaging modalities as MRI, nuclear imaging (SPECT and PET), CT or ultrasound or preferably a combination of these techniques, non-invasive imaging of the kinetic of the drug and/or image guided drug delivery is achievable. In this special issue the current developments in “imaging and treatment of oncological diseases” are described. In particular novel and future imaging agents for nuclear, MR and CT imaging will be explicated. The recent awareness of the advantages in combining imaging modalities linked to the development of new probes, which can be visualized by more than one imaging modality, is discussed in this issue. Furthermore, promising carriers like liposomes, antibodies and peptides to which imaging agents and therapeutic compounds as well can be attached are reviewed in this issue. Also dedicated therapeutic agents and devices that have proven their value in the treatment of specific oncological diseases like bone metastases, thyroid and liver cancer, are discussed in depth. Visualization of these treatment agents is an essential aspect in adequately treating these patients. In addition this theme issue offers insight into the advantages and disadvantages of the above mentioned imaging modalities among which the differences in detection limits and resolution, and will support the concerns that have to be considered by emerging new imaging agents. I would like to thank all authors for their contribution to this special issue. In my opinion this theme issue will give an excellent overview of the “ins and outs” of imaging agents and their explicit position in the battle to conquer cancer.

Originally, nuclear medicine focused on radiopharmaceuticals trapped in organ structures, based on their function, and the presence of disease was seen by the absence of radioactivity. More recently, target-specific radiopharmaceuticals have been developed to visualize and/or treat oncological diseases. Since radiopharmaceuticals have historically a leading position in the search for “molecular imaging”, it would be a waste not to learn from the pitfalls and opportunities that have been and are found during the development of radiopharmaceuticals. This knowledge can be used in the improvement of contrast agents for other imaging modalities like MRI and CT. In this article the aspects that are needed for the use of current and future therapeutic and diagnostic radiopharmaceuticals are described. Especially the production and development of therapeutic and imageable radiopharmaceuticals are demonstrated. MRI or CT can sometimes also image stable isotopes of elements that contain useful radionuclides. This can result in real multimodality imaging. Combining imaging modalities and imaging agents will result in better patient care and can only be advantageous if all departments and institutes will collaborate on their research work. The combination of approaches together with the fast progress in developments in the medical imaging world will result in a bright future for imaging driven therapy of cancer.

Magnetic Resonance Imaging (MRI) is increasingly used in clinical diagnostics, for a rapidly growing number of indications. The MRI technique is non-invasive and can provide information on the anatomy, function and metabolism of tissues in vivo. MRI scans of tissue anatomy and function make use of the two hydrogen atoms in water to generate the image. Apart from differences in the local water content, the basic contrast in the MR image mainly results from regional differences in the intrinsic relaxation times T1 and T2, each of which can be independently chosen to dominate image contrast. However, the intrinsic contrast provided by the water T1 and T2 and changes in their values brought about by tissue pathology are often too limited to enable a sensitive and specific diagnosis. For that reason increasing use is made of MRI contrast agents that alter the image contrast following intravenous injection. The degree and location of the contrast changes provide substantial diagnostic information. Certain contrast agents are predominantly used to shorten the T1 relaxation time and these are mainly based on low-molecular weight chelates of the gadolinium ion (Gd3+). The most widely used T2 shortening agents are based on iron oxide (FeO) particles. Depending on their chemical composition, molecular structure and overall size, the in vivo distribution volume and pharmacokinetic properties vary widely between different contrast agents and these largely determine their use in specific diagnostic tests. This review describes the current status, as well as recent and future developments of MRI contrast agents with focus on applications in oncology. First the basis of MR image contrast and how it is altered by contrast agents will be discussed. After some considerations on bioavailability and pharmacokinetics, specific applications of contrast agents will be presented according to their specific purposes, starting with non-specific contrast agents used in classical contrast enhanced magnetic resonance angiography (MRA) and dynamic contrast enhanced MRI. Next targeted contrast agents, which are actively directed towards a specific molecular target using an appropriate ligand, functional contrast agents, mainly used for functional brain and heart imaging, smart contrast agents, which generate contrast as a response to a change in their physical environment as a consequence of some biological process, and finally cell labeling agents will be presented. To conclude some future perspectives are discussed.

Intravascular iodinated contrast agents are required for a large proportion of computed tomography (CT) studies. Contrast media are indispensable to more clearly differentiate anatomic structures and to detect and characterize abnormalities. Depending on the indication up to 200 ml of these agents are injected during CT. Despite these large amounts adverse effects are rare and have further decreased with the introduction of non-ionic substances. However, it took 10 to 20 years until these non-ionic agents replaced the older ionic agents in clinical practice. In recent years no new substance has been brought to the market. The introduction of rapid scanning using multislice CT technology, however, has led to the development of more sophisticated contrast injection techniques. Current research focuses on optimizing contrast application techniques and on further evaluating the safety profiles of the various substances. The amount of contrast enhancement obtained in individual patients for instance depends on the contrast agent characteristics, such as iodine concentration, and the parameters of the contrast injection protocol, such as iodine flux and iodine dose. Meanwhile, contrast agent characteristics such as osmolality and viscosity play a role in the safety profile of an agent. This paper provides a current overview of CT contrast media, CT contrast dynamics, and CT contrast applications with a special focus on oncological imaging.

Noninvasive imaging techniques like magnetic resonance imaging (MRI), computed tomography (CT) and single photon emission computed tomography (SPECT) play an increasingly important role in the diagnostic workup and treatment of cancerous disease. In this context, a distinct trend can be observed towards the development of contrast agents and radiopharmaceuticals that open up perspectives on a multimodality imaging approach, involving all three aforementioned techniques. To promote insight into the potentialities of such an approach, we prepared an overview of the strengths and limitations of the various imaging techniques, in particular with regard to their capability to quantify the spatial distribution of a multimodal diagnostic agent. To accomplish this task, we used a two-step approach. In the first step, we examined the situation for a particular therapeutic anti-cancer agent with multimodal imaging opportunities, viz. holmium- loaded microspheres (HoMS). Physical phantom experiments were performed to enable a comparative evaluation of the three modalities assuming the use of standard equipment, standard clinical scan protocols, and signal-known-exactly conditions. These phantom data were then analyzed so as to obtain first order estimates of the sensitivity and detection limits of MRI, CT and SPECT for HoMS. In the second step, the results for HoMS were taken as a starting point for a discussion of the factors affecting the sensitivity and detection limits of MRI, CT and SPECT for multimodal agents in general. In this, emphasis was put on the factors that must be taken into account when extrapolating the findings for HoMS to other diagnostic tasks, other contrast agents, other experimental conditions, and other scan protocols.

Radioimmunotherapy (RIT) using radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens has evolved from an appealing concept to one of the standard treatment options for patients with non-Hodgkin's lymphoma (NHL). Inefficient localization of radiolabeled MAbs to nonhematological cancers due to various tumor-related factors, however, limits the therapeutic efficacy of RIT in solid tumors. Still, small volume or minimal residual disease has been recognized as a potentially suitable target for radiolabeled antibodies. Several strategies are being explored aimed at improving the targeting of radiolabeled MAbs to solid tumors thus improving their therapeutic efficacy. In this review, various aspects of the application of radiolabeled MAbs as anti-cancer agents are discussed, and the clinical results of RIT in patients with hematological and various solid cancers (colorectal, ovarian, breast and renal carcinomas) are reviewed.

Radiolabelled peptides have shown to be an important class of radiopharmaceuticals for imaging and therapy of malignancies expressing receptors of regulatory peptides. These peptides have high affinity and specificity for their receptors. The majority of these receptors are present at different levels in different tissues and tumours. This review focuses on the application of regulatory peptides radiolabelled with 67/68Ga , 90Y, 111In or 177Lu. Due attention is given to the current status of research, limitations and future perspectives of the application of these radiolabelled peptides for imaging and radiotherapy. It also covers elements of the basic science and preclinical and clinical aspects in general, however, mostly based on somatostatin receptor-mediated imaging and therapy. New analogues, chelators, radionuclides and combinations thereof are discussed.

The ubiquitin-proteasome pathway plays a central role in the degradation of proteins involved in several pathways including the cell cycle, cellular proliferation and apoptosis. Bortezomib is the first proteasome inhibitor to enter clinical use, and received approval by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma, therefore validating inhibition of the proteasome as an anticancer target. The approval of Bortezomib was based on a large, international, multicenter phase III trial showing its efficacy and safety compared with conventional therapy. Preclinical data also demonstrates the synergistic effect of bortezomib with other chemotherapeutic agents and its ability to overcome drug resistance. Since then several other proteasome inhibitors have been developed. The anti-tumor activities of bortezomib have been attributed to its effect on pro-apoptotic pathways including the inhibition of NF-κB and induction of endoplasmic reticulum stress. However, the molecular mechanisms are not fully understood. In this review, we will summarize the molecular mechanism of apoptosis by bortezomib.

For radiotherapy, biomolecules such as intact antibodies, antibody fragments, peptides, DNAs and other oligomers have all been labeled with radiorhenium (186Re and 188Re). Three different approaches have been employed that may be referred to as direct, indirect and integral labeling. Direct labeling applies to proteins and involves the initial reduction of endogenous disulfide bridges to provide chelation sites. Indirect labeling can apply to most biomolecules and involves the initial attachment of an exogenous chelator. Finally, integral labeling is a special case applying only to small molecules in which the metallic radionuclide serves to link two parts of a biomolecule together in forming the labeled complex. While the number of varieties for the direct and integral radiolabeling approaches is rather limited, a fairly large and diverse number of chelators have been reported in the case of indirect labeling. Our objective herein is to provide an overview of the various chelators that have been used in the indirect labeling of biomolecules with radiorhenium, including details on the labeling procedures, the stability of the radiolabel and, where possible, the influence of the label on biological properties.