SCIENTIFIC BACKGROUND. The enzyme IDO catalyzes tryptophan degradation. IDO can be a potent effector of immunosuppression and of tolerance induction in certain settings; for example, expression of IDO in the placenta maintains maternal tolerance towards the fetus. Tumors create a state of immunologic unresponsiveness (tolerance) toward their own antigens, which allows tumors to escape the host’s immune system. This also imposes a barrier to effective anti-tumor immunotherapy. One molecular mechanism contributing to this tolerance is expression of the immunosuppressive enzyme IDO, leading to inhibition of T-cell response. Expression of IDO by human and mouse antigen-presenting cells inhibits T cell mediated immune responses in vitro and in vivo. Tumor cells transfected with IDO become immunosuppressive in vivo, and expression of IDO has been reported in tumor cells from a variety of human tumors. IDO is also expressed by a population of host antigen-presenting cells (dendritic cells) found in tumor-draining lymph nodes of melanoma, breast cancer, and a variety of other tumors, which may act to create tolerance to tumor antigens. Therefore, IDO may be a primary molecular target for cancer immunotherapy and inhibition of the IDO pathway may assist in breaking tumor tolerance. Studies have shown that the small-molecule 1MT possesses immune-enhancing activity by inhibiting IDO in a variety of animal models. 1MT can inhibit IDO enzyme activity in vitro and can prevent IDO-mediated immunosuppression in vivo. 1MT has also been shown to be synergistic with a number of commonly used chemotherapeutic agents. Thus, 1MT may potentially be used as a novel immune modulator in cancer immunotherapy.
SCIENTIFIC BACKGROUND. Base-excision repair (BER) is a key resistance mechanism employed by cancer cells to survive chemotherapy-induced DNA damage, and inhibiting BER improves the therapeutic index of these agents in preclinical models. TRC102 (methoxyamine hydrochloride) is an inhibitor of BER with a unique mechanism of action. TRC102 exerts its effect by rapidly and covalently binding to chemotherapy-induced apurinic/apyrimidinic (AP) sites generated by glycosylase removal of abnormal bases. TRC102-bound DNA is no longer a substrate for BER enzymes and is instead irreversibly cleaved by topoisomerase II resulting in double-strand DNA breaks that trigger cellular apoptosis. The induction of apoptosis by TRC102 is selective for cancer cells because they express high levels of topoisomerase II. In normal cells with low topoisomerase II expression, TRC102-bound DNA is predominantly excised and replaced with normal DNA by the long patch DNA repair system. The efficacy of TRC102 is independent of tumor O-6-methylguanine-DNA methyltransferase (MGMT) expression, mismatch repair status, or p53 status. TRC102 is synergistic with a wide variety of cancer therapies including antimetabolites, oxidizing agents, alkylating agents, and poly ADP ribose polymerase (PARP) inhibitors. The active molecule is a small organic amine that is highly water soluble and nearly completely bioavailable after oral administration.
SCIENTIFIC BACKGROUND. Tumors rely on angiogenesis to grow and metastasize, and angiogenesis inhibitors have demonstrated clinical benefit in patients with cancer. CD105 is a member of the transforming growth factor beta (TGF-b) receptor family that is selectively expressed by proliferating endothelial cells and is essential for endothelial cell proliferation. Expression of CD105 is induced by cellular hypoxia through hypoxia-inducible factor-1-. CD105 is highly expressed on tumor vessel endothelium of all types of solid cancer and exerts its effect by modulating the signaling of multiple TGF-b receptor signaling complexes. In the absence of CD105, TGF- b receptor activation inhibits endothelial cell proliferation and angiogenesis. However, in the presence of CD105, TGF-b receptor signaling is modified to promote endothelial cell proliferation and angiogenesis.
SCIENTIFIC BACKGROUND. Clinical depression is one of the most common mental disorders. The condition is characterized mostly by a combination of a number of symptoms such as pessimism, loss of interest or pleasure, major weight change or change in appetite, fatigue or loss of energy, sleep disorder, loss of concentration, feelings of guilt, thoughts of death, etc. that last at least two weeks. In various studies, the average incidence of this disorder worldwide is between 5% and 15% annually. This situation adversely affects many areas of a person’s life, such as family, work and studies, quality of life and general health. It can be a considerable burden on the health services and at the same time can cause major functional damage, including loss of ability to work and alcoholism. The most accepted treatments in situations of depression are currently therapeutic treatment and psychotherapeutic treatment (on their own or in combination). However, there are cases in which these treatments do not lead to the desired results and to the patient’s remission (1-3). Between 20% and 40% of patients do not respond to the existing therapeutic treatment or to a combination of therapeutic treatment and psychotherapeutic treatment (4). In cases of persistent depression, patients who do not respond to the standard treatment occasionally switch to treatment with electro convulsive therapy. This treatment is considered the most effective (5) but is administered under general anesthetic, and apart from the risks of the anesthesia, it involves side effects, including a risk of developing cognitive disorders and permanent damage (6). Transcranial Magnetic Stimulation (TMS) is a non-invasive method in which the nerve cells in specific regions of the brain can be stimulated. This method, which has been in use for 20 years, works by means of a coil into which flows a pulsating electrical current. During pulsation, the current in the coil causes electromagnetic induction that permeates into the brain and creates an electrical field that arouses the nerve cells in the brain in the region at which the coil is directed. In the last few years, use has been made of Repetitive Transcranial Magentic Stimulation (rTMS) in the treatment of depression, whereby the TMS device is operated at a number of consecutive pulses at a certain frequency. This treatment is non-invasive, is administered when the patient is fully conscious, and has few side effects. In depressive patients with no psychotic component it is ev...
