Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 7, Issue 4, 2007

In this second part of the theme issue “Imaging and Treatment of Oncological Diseases” several image guided radionuclide based treatment approaches are discussed in depth: the renowned iodine-131 therapy for thyroid cancer is reviewed and also two novel treatment options for liver cancer patients. Furthermore, a review on bone seeking radiopharmaceuticals and one on liposomes for multimodal imaging are included. In these articles a clear strong point of nuclear medicine is demonstrated: radiopharmaceuticals can often be used to image and to treat disease. The article on liposomes is devoted to both nuclear imaging and magnetic resonance imaging (MRI). Currently, a very popular issue in medical imaging is the development of MR imaging agents in the frame work of “molecular imaging”. However, the number of nonradioactive imaging agents available is still very low compared to the radioactive imaging agents that are on the market. One part of the explanation is the one century of radioisotope research. The rest of the explanation is that research in MRI and CT has been mostly aimed on the apparatus itself while research in the field of nuclear medicine is aimed on the development of radiopharmaceuticals. The gamma camera is just used as a tool to visualize the distribution of the radioactive compounds. Recently, some progression has been made in the development of agents for MR imaging; nowadays a few new imaging agents have been clinically introduced. The most widely used are the iron oxide compounds. Other examples are liposomes and micelles labeled with iron, gadolinium, dysprosium or holmium. Most of these imaging agents are lanthanides which have useful properties for MR and can be easily incorporated in or attached to all kinds of carriers. Some of the new lanthanide systems are described in the article on nanocarriers by Koning and Krijger and in the article on radioembolization treatment of liver cancer by Vente et al. Imaging of drugs could be applied to personalize medicine. This would entail that each patient receives an individually designed therapy regarding dose, timing, and treatment response assessment. The amount of imaging compounds needed for a detectable signal or signal change in MRI is enormous compared to the quantities used in nuclear medicine. In the article of Seevinck et al., in part I of this theme issue, the factors affecting the sensitivity and detection limits of MRI and CT were compared to nuclear imaging. While nuclear imaging will certainly remain superior in detecting minute tracer amounts of imaging agents, it is expected that especially MRI will further increase the ability to depict low amounts in the patient. Ultimately, combining imaging modalities and the emerging development of multimodal imaging agents will overcome the shortcomings of each individual imaging technique and will radically advance the time of diagnosis and improve the treatment success in oncological patients. I would like to thank all authors for their contribution to this special issue and especially all expert referees that have reviewed the articles of this theme issue.

Many patients with cancer develop symptomatic skeletal metastases at an advanced stage of their disease. Skeletal metastases are often complicated by pain. They cause considerable morbidity and mortality. Besides analgesics, treatment options include external beam radiotherapy, bisphosphonates, chemotherapy, surgery and bone seeking radiopharmaceuticals. Pain palliation with bone seeking radiopharmaceuticals has proved to be an effective treatment modality in patients with metastatic bone pain. Radiopharmaceuticals bind to the bone matrix in areas of increased bone turnover, due to a metastatic response. Beta rays from the specific radionuclide, bound to its carrier ligand, result in the therapeutic effect. Various radiopharmaceuticals have been developed for this purpose. All have their own characteristics. The radiopharmaceuticals Samarium-153-ethylenediaminetetramethylenephosphonic acid (153Sm-EDTMP) and Strontium- 89-Chloride, which are approved in the USA and Europe, as well as the not universally approved Rhenium-186-hydroxyethylidenediphosphonic acid (186Re-HEDP), will be discussed in greater detail. Depending on the half-life and radiation energy of the specific radionuclide, they exert a different effect and toxicity profile. In most cases, bone marrow toxicity is limited and reversible, which makes repetitive treatment relatively safe. Several studies have shown encouraging clinical results of palliative therapy using bone seeking radiopharmaceuticals, with an overall reported pain response rate in the order of ± 70-80% of patients. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life. Additionally, new therapeutic strategies hold the promise of enhancement of the palliative and anticancer effects of this form of therapy.

In 1942, Dr. Seidlin of the Memorial Hospital in New York was faced with a 51-year- old patient who had undergone a thyroidectomy in 1923 [1]. At the time, the histologic diagnosis was a ‘malignant adenoma’ of the thyroid. In 1938 the patient returned with overt signs of thyroid hyperfunction (hyperthyroidism) and lower back pain. A metastasis was found in the lower spine, and surgically removed. Over the next years the patient remained hyperthyroid and developed more bone metastases. At the time of presentation to Dr. Seidlin, the patient was in an extremely poor condition: he was in severe pain, severely hyperthyroid, and severely underweight. At this time radioiodine therapy had just reached the clinical arena. In 1937 Hertz, Roberts and Evans investigated the rabbit's thyroid function using I-128 [2]. Later they pursued therapeutic goals for e.g. Graves' disease using I-130. They used dosages that we now know would have been merely diagnostic if it were not for a probable 10% I-131 contaminant [3]. Livingood and Seaborg identified I-131 as a separate isotope. In 1942 two groups independently reported on the successful treatment of hyperthyroidism with I-131 sodium iodide [4,5]. Radioiodine was so rare that it was recovered from the urine, purified and re-administered to the patient. The patient responded favourably to the radioiodine treatment, and he received several more courses of I-131. Geiger-counter examination of the patient revealed two previously unknown metastases, thereby indicating the diagnostic capabilities of radioiodine. The patient did very well on these courses: the hyperthyroidism subsided, the body-weight kg increased from 38 to 53 kilograms, and the pains diminished. This report of a potential cure for terminally ill patients fuelled the public imagination to a degree that it hit the political agenda. Effective on August 1, 1946, the Atomic Energy Act (AEA) made radioisotopes available for medical use in the USA. This date marks the beginning of ‘atomic medicine’, later named nuclear medicine.

Cancer often remains an incurable disease, despite significant progresses in diagnosis and treatment that have been made. Specifically, the use of nuclear medicine in oncology is greatly contributing to both imaging and therapy aspects. Targeted therapies are a major field of interest since it increases efficiency and reduces side effects. Brachytherapy is among the most valuable of recent developments for treating localized tumours resulting in improvements in improved quality of life. This is primarily because it irradiates cancerous cells most exclusively while barely effecting healthy tissue. The use of radiochemicals implies specific management for production, transport and handling that have limited the development of this technique. This review article describes brachytherapy and their latest developments. Furthermore, alternative activation methods for the production of radioisotopes and a novel delivery system for targeted multi-therapy by using PLA-ferrite nanospheres are described.

Lipid-based nanocarriers have proven successful in the delivery of mainly chemotherapeutic agents, and currently they are being applied clinically in the treatment of various types of cancer. These drug delivery systems achieve increased therapeutic efficacy by altering the pharmacokinetics and biodistribution of encapsulated drugs, resulting in decreased drug toxicity and enhanced accumulation in tumor tissue. This increased accumulation is due to the relatively leaky immature vasculature of a tumor. After the clinical relevance of such drug delivery systems was demonstrated, research in this area focused on optimization, both by cell specific targeting and including controlled and triggered release concepts within the carrier. These more advanced targeted nanocarriers in general have clearly shown their potential in various animal tumor models and await clinical application. The development of targeted nanocarriers in which therapeutic and imaging agents are merged into a single carrier will certainly be of importance in the near future. Indeed, scientists active in the field of imaging (e.g. nuclear and magnetic resonance imaging) have already started to exploit nanocarriers for molecular imaging. Image-guided drug delivery using these multifunctional nanocarriers, containing therapeutic and imaging agents, will ultimately allow for online monitoring of tumor location, tumor targeting levels, intratumoral localization and drug release kinetics prior and during radio- and/or chemotherapeutic treatment. This review describes the current status and challenges in the field of nanocarrier-aided drug delivery and drug targeting and discusses the opportunities of combining imaging probes with these drug carriers and the potential of these multifunctional lipid-based nanocarriers within image-guided drug delivery.

Primary and secondary liver cancer have longtime been characterized by an overall poor prognosis since the majority of patients are not candidates for surgical resection with curative intent, systemic chemotherapy alone has rarely resulted in long-term survival, and the role of conventional external beam radiation therapy has traditionally been limited due to the relative sensitivity of the liver parenchyma to radiation. Therefore, a host of new treatment options have been developed and clinically introduced, including radioembolization techniques, which are the main topic of this paper. In these locoregional treatments liver malignancies are passively targeted because, unlike the normal liver, the blood supply of intrahepatic tumors is almost uniquely derived from the hepatic artery. These internal radiation techniques consist of injecting either yttrium-90 (90Y) microspheres, or iodine-131 (131I) or rhenium-188 (188Re) labeled lipiodol into the hepatic artery. Radioactive lipiodol is used exclusively for treatment of primary liver cancer, whereas 90Y microsphere therapy is applied for treatment of both primary and metastatic liver cancers. Favorable clinical results have been achieved, particularly when 90Y microspheres were used in conjunction with systemic chemotherapy. The main advantages of radiolabeled lipiodol treatment are that it is relatively inexpensive (especially 188Re-HDD-lipiodol) and that the administration procedure is somewhat less complex than that of the microspheres. Holmium-166 (166Ho) loaded poly(L-lactic acid) microspheres have also been developed and are about to be clinically introduced. Since 166Ho is a combined beta-gamma emitter and highly paramagnetic as well, it allows for both (quantitative) scintigraphic and magnetic resonance imaging.

The respiratory epithelium expresses the cholinergic system including nicotinic receptors (nAChRs). It was reported that normal human bronchial epithelial cells (BEC), which are the precursor for squamous cell carcinomas, and small airway epithelial cells (SAEC), which are the precursor for adenocarcinomas, have slightly different repertoires of nAChRs. Studies shown that nAChRs expressed on lung carcinoma or mesothelioma form a part of an autocrine-proliferative network facilitating the growth of neoplastic cells; others demonstrated that nicotine can promote the growth of colon, gastric, and lung cancers. Nicotine and structurally related carcinogens like NNK [4-(methylnitrosoamino)- 1-(3-pyridyl)-1-butanone] and NNN (N'-nitrosonornicotine) could induce the proliferation of a variety of small cell lung carcinoma cell lines and endothelial cells and nicotine in non-neuronal tissues -including lung- induces the secretion of growth factors (bFGF, TGF-α, VEGF and PDGF), up regulation of the calpain family proteins, COX-2 and VEGFR-2, causing the eventual activation of Raf/MAPK kinase/ERK (Raf/MEK/ERK) pathway contributing to the growth and progression of tumors exposed to nicotine through tobacco smoke or cigarette substitutes. It has been demonstrated that nicotine promotes the growth of solid tumors in vivo, suggesting that might induce the progression of tumors already initiated. While tobacco carcinogens can initiate and promote tumorigenesis, the exposure to nicotine could confer a proliferative advantage to early tumors but there is no evidence that nicotine itself provokes cancer. This is supported by the findings that nicotine can prevent apoptosis induced by various agents - such as chemotherapeutic in NSCLC, conferring a survival advantage as well.

Apoptosis is a genetically programmed process of controlled and orderly cell suicide, which is critical for multicellular organisms during development and tissue homeostasis. In cancer, the ratio of apoptosis to cell division is altered, resulting in a net gain of malignant tissue. Tumor cells may acquire resistance to apoptosis by the expression of anti-apoptotic proteins, or by the down-regulation or mutation of pro-apoptotic mediators. In the classic pathway of apoptosis, this process is primarily coordinated by activation of caspases. Decreased expression of caspases inversely correlates with the aggressiveness of cancer. Increased activity of caspases renders cancer cells susceptible to chemoradiotherapeutic modalities. Thus, caspase activity is pivotal in carcinogenesis. The functions of activated caspases are inhibited by the binding of inhibitors of apoptosis (IAPs). The function of IAPs is regulated by pro-apoptotic protein Second Mitochondria-Derived Activator of Caspases (Smac) or Direct IAP Binding Protein with low isoelectric point, pI (DIABLO). Induction of apoptosis leads to increased mitochondrial permeability to Smac/DIABLO, which adheres to IAPs inhibiting their caspase-binding activity. The role of Smac/DIABLO, therefore, may have significant diagnostic and therapeutic features in carcinogenesis. The role of Smac/DIABLO in colorectal carcinogenesis is ill defined. Data continues to accumulate to suggest that decreased levels of Smac/DIABLO may be important in chemoradiation-resistance to apoptosis in advanced colon cancer. The aim of this review is to provide the available evidence of the role of Smac/DIABLO in colon carcinogenesis.

Telomerase is an attractive target for anti-cancer therapeutics due to its requirement for cellular immortalization and expression in greater than 85% of human neoplasms. Though initially promising, strategies that inhibit telomerase with either small molecules or antisense oligonucleotides have a major limitation, namely the lag time required for telomere shortening before cellular effects are attained. As alternative approaches, immunotherapy and gene therapy have been tailored to exploit, rather than antagonize telomerase expression and/or activity. Immunotherapy requires the presence of the catalytic subunit of telomerase, hTERT, to elicit an immune response directed towards hTERT peptide-presenting cells. hTERT promoter-driven gene therapy and mutant telomerase RNA (hTR) gene therapy depend on the innate telomerase activity of cancer cells to drive the expression of pro-apoptotic genes and to synthesize mutated DNA sequences onto telomeres, respectively. In addition, we will discuss telomestatin, a G-quadruplex binding ligand that may exert anti-proliferative effects independently of telomere shortening. In this review, the progress, advantages, and limitations of these strategies in the ongoing effort to develop clinically relevant telomerase-based cancer therapeutics will be examined.