Current Pharmaceutical Design - Volume 8, Issue 20, 2002

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide / lanreotide analogs as tumor tracers in nuclear medicine. Other (nontumoral) potential indications for SSTR scintigraphy are based on an increased lymphocyte binding at sites of inflammatory or immunologic diseases such as thyroidassociated ophtalmology.The vast majority of human tumors seem to over-express the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to overexpress more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OctreoScan) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In / 90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90 Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPADPhe1- octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a “higher” high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2 (Kd 0.1-1 nM). Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, such as 99mTc-depreotide (NeoSpect, NeoTect). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or nonsmall cell lung cancer (99mTc-depreotide), indicating high diagnostic cabability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. Beneficial results were reported for highdose treatment with 111In-DTPA-DPhe1-octreotide, based on the emission of Auger electrons. The Phase IIa study “MAURITIUS” (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study) showed in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy / GBq 90 Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the “MAURITIUS” study, cummulative treatment doses up to 200 mCi 90 Y-DOTA-lanreotide were given as short-term infusion. Overall treatment results in 70 patients indicated stable tumor disease in 35% of patients and regressive tumor disease in 10% of tumor patients with different tumor entities expressing hSSTR. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90 Y-DOTA-lanreotide treatment, were reported. 90Y-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore be superior for treatment in patients with neuroendocrine tumors. However, there is only limited excess to long-term and survival data at present. Potential indications for 90 Y-DOTA-lanreotide are radioiodine-negative thyroid cancer, hepatocellular cancer and lung cancer. Besides newer approaches and recent developments of 188Re-labeled radioligands, no clinical results on the treatment response are yet available.In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm their potential use in diagnosis as well as “proof-ofprinciple”for therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy. Ongoing developments may result in peptides more suitable for this kind of receptor-targeted radionuclide therapy.

From the prospective of a major oncology center in the United States, somatostatin analog radiopeptides currently have limited diagnostic and therapeutic utility. Diagnostic modalities utilitizing Somatostatin Receptor Imaging are now commercially available and the role of this type of method is currently being evaluated. Unlike the unique properties of thyroid tissue facilitating I-131 uptake, targeting of other tissues has required a carrier for the nuclide. Somastostatin peptide analogs have proved attractive based on the ubiquity of distribution and up-regulation in diseased tissue but prospective data is currently scarce. Interest in therapeutic applications of somatostatin analogs as carriers of yttrium, indium and more recently rhenium have resulted in trials with these agents both for endocrine and non-endocrine tumors. At this time, insufficient data exists to justify the indication of “first-line” therapy. The principles of Somatostatin Receptor Imaging and radiotherapy are discussed in this article along with the current status of these modalities in clinical practice as viewed by the author.

Until recently, imaging acute thrombus, especially the very prevalent condition of acute deep vein thrombosis relied on conventional imaging techniques utilizing either ultrasonography or contrast venography. The former procedure is limited by accuracy and the latter by technical considerations. Newer modalities such as magnetic resonance and computed tomographic scanning are yet to be validated in a prospective manner. Recent advances in the understanding of the pathogenesis of acute clot at the molecular level have suggested new avenues for detection of the acute thrombotic process based on the biomolecular behavior of components of the clotting process including the formed element of the blood, the platelet. Expression of a receptor on platelets unique to acute thrombosis and synthesis of small peptide ligands with high specificity for that receptor have suggested a new venue for evaluation of acute venous thrombotic disorders. The challenges of ligand synthesis for the integrin glycoprotein receptors on platelets are discussed along with the difficulties of incorporation of a convenient nuclide for imaging purpose, 99mTc. The absence of specificity for acute clot in established “gold standard” tests including contrast venography suggests that small peptide directed ligand-receptor imaging may provide superior information based on the biomolecular behavior of the clotting process.

Globally, lung cancer has risen to the leading cause of cancer mortality in both sexes. Currently, the only potentially curable stage of the disease is the pulmonary nodule. Since numerous studies have documented that in any population of nodules only approximately fifty percent ultimately prove to be neoplastic, non-invasive evaluation of nodules to reduce surgical morbidity, mortality and cost is desirable. Recent nuclear medicine imaging modalities have shown promise in the accurate non-invasive characterization of pulmonary nodules. These new technologies exploit the biomolecular alterations of neoplastic cells. The somatostatin receptor is relatively over-expressed in pulmonary neoplastic tissue when compared to most benign tissue processes. A somatostatin analog-technetium ligand (99mTc depreotide) has shown significant promise in the rapid, convenient, accurate and cost effective characterization of lung nodules with conventional gamma camera systems. The development of this agent required synthesis of a somatostatin receptor ligand of high affinity for the receptor subtypes operative in pulmonary neoplasia and the incorporation of technetium without loss of pharmacore specificity.

A wealth of both clinical and pre-clinical data has strongly implicated the eosinophil in the pathogenesis of asthma, highlighting this cell type as a potential target for novel anti-inflammatory approaches to asthma therapy. The Th2 lymphocyte derived cytokine Interleukin-5 (IL-5) has emerged as the key regulator of eosinophil production, thus identifying IL-5 as the principal molecular target for therapeutic intervention. This review highlights both the pharmaceutical approaches, and the major challenges, to the identification of small molecule and protein antagonists of the IL-5 receptor. Using examples of known inhibitors we discuss their current status and highlight the major development hurdles in progressing these molecules into the market place.

In the complex pathogenesis of airway inflammation seen in asthma, several cytokines are recognized to play a crucial role. Modulation of the effect of these cytokines can provide alternative and more specific treatment approach to currently widely-used systemic immunosuppression by glucocorticoids. Theoretically, cytokine modulation can be achieved via several pathways, including inhibition of released cytokines by using antibodies or soluble receptors, blocking cytokine receptors, inhibiting signal transduction or preventing cytokine gene transcription. Also, some cytokines are known to possess anti-inflammatory effects in allergic inflammation, being thus themselves potentially used as a therapeutic agent. The current review discusses the present knowledge on the involvement of cytokines in the pathogenesis of allergic asthma and the experience on modulation of the effect of these cytokines in clinical situations.

Several chronic inflammatory airway diseases are characterized by an increased number of neutrophils in the airways. There is evidence that the recruitment of these neutrophils can be controlled by certain T-lymphocytes. However, the mechanisms behind this T-cell control of airway neutrophilia are poorly understood. In this review, we summarize the evidence that interleukin (IL)-17 released from T-lymphocytes of the CD45RO+ subset can link the activation of these T-cells to the recruitment and activation of neutrophils. This evidence suggests that pharmacotherapeutical modulation of neutrophilic airway inflammation can be achieved using several different strategies, including inhibition of IL-17 production by cAMP elevating agents or certain nuclear factor inhibitors, neutralization of released IL-17 protein by specific anti-IL-17-antibodies, blockade of the IL-17 receptor as well as inhibition of certain MAP kinases mediating the post receptor effects of IL-17 in airway cells. Additional studies on animals in vivo and patients, respectively, are needed to further evaluate the pharmacotherapeutical potential of these strategies.

Asthma is characterised by a chronic inflammatory process involving the airway wall leading to airflow limitation and bronchial hyperresponsiveness. This review describes the cellular molecular events underlying airway inflammation and remodelling in asthma and focuses on the distinct mechanisms of action of corticosteroids in beta agonists in asthma pathophysiology. In particular it discusses the evidence from studies both in vitro and in vivo to suggest that there is a complimentary beneficial interaction of these agents on the asthma process.

NK cells have been associated with immune surveillance of tumor cells and defense mechanisms against various pathogens. However, by their capacity for immunoregulation NK cells may also play a role in determining the response to allergens. The novel possibility that NK cell activity may in part decide development of allergic airway inflammation and thus potentially be involved in the inception of asthma is discussed in this review article.