Recent Patents on Anti-Cancer Drug Discovery - Volume 2, Issue 3, 2007

Cancer is one of the leading causes of mortality in the world. This is a complex disease involving many steps with proper signalling pathways. Early detection and treatment of cancers have increased survival and improved clinical outcome. However, novel strategies based on new interesting targets are needed to improve the conventional treatments. A few years ago, it appeared that some particular transmembrane proteins, ion channels, may be involved in the development of the disease. Since then, their role in cancer cell properties such as proliferation, migration and invasion begins to be unravelled. These proteins have been widely studied in non cancerous cells as well as in pathologies involving excitable cells and thus, their pharmacology are quite well known. In this review, we summarize the present knowledge about the role of different ion channels in some aspects of the development of tumours, mainly proliferation, migration and invasion. A particular emphasis is done on promising new patents.

The androgen receptor (AR) plays a central role in the initiation and growth of prostate cancer. Androgen deprivation therapy (ADT) has been a gold standard for advanced prostate cancer for decades. Unfortunately, suppressive effects of ADT do not last long and hormone-refractory prostate cancer develops within several years. In spite of extensive research on mechanisms of hormone-independent growth of prostate cancer, there are few effective treatment options for recurrent tumors and most patients die from the disease in a short period of time. Accumulating evidence suggests that the AR signaling system remains intact and activated despite low levels of androgens in hormone-resistant prostate cancer. Currently, modifications to the AR via mutations, amplification and phosphorylation have been proposed as underlying mechanisms of hormone-resistance of prostate cancer cells. In addition, changes in AR cofactors are implicated in ligand-independent activation of AR signaling. Thus, the development of novel and more effective treatment modalities targeting the AR and AR-related molecules may provide better management of androgen-independent prostate cancer. Although recent patents on the AR related to prostate cancer are focused on antiandrogens, future trend will be shifted to agents or methods suppressing molecules or pathways that activate AR signaling in low androgen environments.

Potassium channels constitute a large and heterogeneous family with more than eighty genes which encode membrane proteins that control membrane potential. In addition to nerve and cardiac action potential, these proteins are involved in a number of physiological processes including volume regulation, apoptosis, immunomodulation and differentiation. Many potassium channels have been related to proliferation and cell-cycle progression in mammalian cell lines and certain potassium channels show impaired expression in cancer cells and tumours. In addition, in some cases a correlation has been established between the protein expression levels and the grade of malignancy of the tumour. Many drugs have been found to inhibit both K+ channel activity and cell-cycle progression. Since potassium channels may play a pivotal role in tumour cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies. The increasing list of recent patents, covered in this review, shows the relevance of this emergent subject.

While most anticancer agents are small molecular weight compounds that inhibit specific steps in the pathways contributing to cancer growth, or monoclonal antibodies that target specific antigens hyperexpressed in cancer cells, recent efforts have also been directed towards bacterial pathogens that are known to allow cancer regression. Consequently, patents that cover the construction or characterization of specific bacteria, with or without additional cloned genes, are available. This review is, however, focused on patents that claim bacterial proteins as potential anticancer agents. In particular, we describe two bacterial proteins that demonstrate both anticancer and antiviral, and often antiparasitic, activities, and therefore the patents cover multiple aspects of the potential use of such bacterial proteins in the treatment of not only cancer but also malaria or other parasitic diseases and HIV/AIDS and similar viral diseases. We also briefly discuss patents that cover the use of CpG-rich DNA, including bacterial DNA, as potential anticancer agents.

The purpose of this study was to determine the permeation of the hydrophilic compound 5-fluorouracil through human epidermal membranes, Ehrlich Ascites Carcinoma (EAC) cells were used as a model cell line to evaluate the cytotoxic concentration and anti-tumor activity of 5-fluorouracil (5-FU) through transdermal drug delivery for tumors. Cytotoxicity was assessed by exposing cell suspension to increased concentration of drug from 20-100 μg/ml and measuring the viable cell count by tryphan blue exclusion method. Results confirmed that 100 μg/ml of 5-FU was cytotoxic. The increase in the life span (ILS) was 87.05% with maximum survival time of 30.5±1.87 days. For 5-fluorouracil monolithic matrix transdermal patch, the results were statistically significant (p<0.05) compared to untreated control, anti-tumor activity was very effective compared to intravenous therapy. Patches did not show any sign of erythema, vesiculations or bullaous reaction. Mean cumulative skin irritation and adherence scoring for both animal and humans proved that none of the irritation sensitization reactions score were zero and less than one, while good adherence score was 0, with complete adherence to the skin, without leaving any adhesive residue on skin with scores = 0 in human subjects. Transdermal patches showed 100% flatness, thickness 150±0.03 mm, good content uniformity, folding endurance (>500 foldings), smoothness, transparency, flexibility and appearance. Pharmacokinetic studies of 5-FU transdermal patch in rabbits showed half-life 95±0.5 min, Cmax (ng/ml) 863.25,AUC0-α (ng/ml/h)1567±36 and Tmax(h) 1.5 with controlled release for 24 h which was very significant (p<0.001) compared to intravenous route. Recent patents has been reported for suitable treatment of tumors and cancer, by topical and transdermal applications. Velcro protection jackets were suitable for this study and protected our applied transdermal patched from being licked, scratched and rubbed off.

The aim of this paper is to analyze merits and demerits of methodological approaches designed for investigations of erythrocyte aggregation - a process, which plays a crucial role in rheological and transport properties of blood. Ideally, erythrocyte aggregation should be characterized in terms of the time-dependent gyration radius of the aggregates and their fractal dimension. Among various experimental techniques suggested so far, only imaging analysis meets this requirement. However, because this technique is designed for investigations of the aggregation process in thin layers of dilute erythrocyte suspensions, aggregation data are affected by cell-wall interactions and, in addition, problems arise when attempts are made to extend these data to whole blood. Interpretation of results obtained by light scattering techniques faces problems associated with effects of multiple scattering, a design of experimental setups and the wavelength on the kinetics of recorded signals. A method based on electric and dielectric properties of blood is advantageous over other methodological approaches, because it provides reliable information about time-dependent and steady-state size and morphology of the aggregates at physiological hematocrits. A common drawback of most methodological approaches is that interpretation of experimental results is based on simplified theoretical models of blood. To avoid complicated physical problems posed by optical, ultrasound, electrical and dielectrical properties of blood, it is suggested to use the adhesion energy as a measure of RBC aggregability.

The efficacy of Hyperthermia and Caelyx as single modalities of therapy in progressed and refractory cancer of different primary sites is well known. Nevertheless, it remains question mark whether they can work together to that direction. We have recently published a paper which demonstrates some excellent results in treatment of recurrent breast cancer with hyperthermia in conjunction with Caelyx and radiotherapy. The mechanism of action of those different therapeutic options and a review in literature are presented in this paper. Despite the limited number of studies, they all show that the combined treatment is effective and well tolerated. It would be interesting to mention another treatment patent of cancer which can be done by a combination of non-ionizing radiation and androgen deprivation. Also, combined therapy for tumors and tumor metastases comprised administration of integrin ligands and co-therapeutic agents have synergistic efficacy in isolated organ perfusion. Finally, the treatment of solid tumors can be done by glycolytic inhibitors.

Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. The application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of many ongoing research projects. Radionuclide imaging modalities (single photon emission computed tomography, SPECT; positron emission tomography, PET) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. Generator produced isotopes, such as 99mTc and 68Ga, are readily available and affordable. 99mTc (t1/2=6 hr; 140 keV) is used for SPECT and 68Ga (t1/2=68 min; 511 keV, 89%) is used for PET. 99mTc- and 68Ga-labeled agents using various chelators have been synthesized and their potential uses to assess tumor targets have been evaluated. Molecular targets labeled with 99mTc and 68Ga can be utilized for the prediction of therapeutic response, monitoring tumor response to treatment and aiding in the differential diagnosis of tumor versus non-tumor tissue. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia, and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics was demonstrated.

Anti-cancer drug development is a major area of research. Monitoring of response to newer anti-cancer drugs has undergone an evolution from structural imaging modalities to targeting functional metabolic activity at cellular level to better define responsive and non-responsive cancerous tissue. This review article highlights the contribution of Positron Emission Tomography (PET) in this field. PET holds a promising role in the future by providing us information pertaining to the drugs effectiveness early in the course of therapy, so that side effects and expenses can be reduced substantially. PET has been used to measure changes in drug induced metabolism, cellular proliferation and tissue perfusion. Also changes induced by immuno-modulating drugs such as apoptosis, telomere activity, growth factor levels and many more can be studied using specific radiolabelled PET tracers whereas conventional imaging modalities which detect changes in tumor size and residual tissue histopathology may not prove useful in such scenario. In future, most PET scanners will be replaced by Hybrid PET-CT scanners, which provide functional and structural information in the same setting. In addition, PET-CT improves characterization of equivocal lesions and decreases interobserver variability. The most important recent patents concerning role of PET in drug development have been presented.

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