Tumor-specific Signal Research Articles

Strategies to optimize the use of targeted agents for tumor therapy

In recent years the traditional treatment spectrum of tumors--chemotherapy or radiotherapy--has been extended with immune-modulating strategies. For some tumors, clinical responses have been observed but for numerous others no satisfactory approach has been established. Many new agents have been developed; the targeted or smart drugs modulate a constantly growing list of tumor-specific signal pathways and represent an enormous hope for cancer patients. The clinical evaluation of these targeted drugs alone or in combination also presents an enormous challenge. Since the number of possible combinations of targeted drugs seems almost limitless, an accurate strategy for determination of success-promising combination patterns for the individual cancer patient is of special importance.

Gonadotropin-Releasing Hormone Type II Antagonists Induce Apoptotic Cell Death in Human Endometrial and Ovarian Cancer Cells In vitro and In vivo

In human endometrial and ovarian cancers, gonadotropin-releasing hormone type I (GnRH-I), GnRH-II, and their receptors are parts of a negative autocrine regulatory system of cell proliferation. Based on a tumor-specific signal transduction, GnRH-I and GnRH-II agonists inhibit the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in down-regulation of cancer cell proliferation. Induction of apoptosis is not involved. In this study, we show that treatment of human endometrial and ovarian cancer cells with GnRH-II antagonists results in apoptotic cell death via dose-dependent activation of caspase-3. The antitumor effects of the GnRH-II antagonists could be confirmed in nude mice. GnRH-II antagonists inhibited the growth of xenotransplants of human endometrial and ovarian cancers in nude mice significantly, without any apparent side effects. Thus, GnRH-II antagonists seem to be suitable drugs for an efficacious and less toxic endocrine therapy for endometrial and ovarian cancers.

Analysis of brain tumor specific signal transduction by proteomic differential display

Recent advances of innovative technologies and valuable data bases for proteome analysis enable us to identify extremely miner but important cellular proteins that related to the pathogenesis, with high throughput and quantitative manner. We established the differential analysis method with the combination of proteomic (2D-DIGE and cICAT/iTRAQ) and transcriptomic (DNA array) techniques using same brain tumor samples that show no pathological differences but significant variations to the chemotherapies, and tried to extract and identify the specific cellular signal cascade related to the chemotherapy sensitivities. For the basic information of human brain proteins, proteome database of brain tissues/cells were constructed with their 2D images and linked to the other brain database. After all of the differential analysis between chemotherapy sensitive and insensitive tumors using above technologies, the significant proteins identified were assembled, integrated, and subjected to the cellular signal network analysis. In the case of anaplastic origodendroglioma/astrosytoma: AOG, a series of proteins that changes their expressions and post-translational modification statuses, in relation to the tumor stages or chemotherapy sensitivities, were quantitatively identified. As glioma specific proteins, 738 proteins were identified in total, and 201 were related to chemotherapy sensitivities in the group of anaplastic gliomas. Using these protein data sets, the activated cellular signals in the chemotherapy insensitive glioma were extracted by the network analysis. They include several unknown signal cascades in gliomas, such as signals related to the specific cell cycle, apoptosis, and cell adhesions. These newly established differential analysis and data mining methods will be useful not only for finding of diagnostics for gliomas, but also for those of other brain diseases.

Peripheral Blood Monoclonal B-Cells Predict the Event Free Survival in Multiple Myeloma

Reinfusion of myeloma progenitor cells may contribute to relapse of multiple myeloma after autologous stem cell transplantation. The aim of our study was to investigate whether monoclonal B-cells are present in the apheresis product and to evaluate the clinical relevance of these cells. Leukapheresis products of 55 patients were purged with anti-B-cell-Monoclonal antibodies (MoAbs) and immunobeads. Monoclonal B-cells were found in 85% of patients within the B-cell population. In one third of all myeloma patients, the majority of B-cells was represented by monoclonal myeloma progenitor B-cells, whereas in two thirds of patients monoclonal cells only represented a small part of the entire B-cell population. As shown by sequence analysis, monoclonal precursor B-cells and malignant plasma cells had the identical genetic CDR III sequence. The purging efficacy, using a negative selection system, was a median of 3 logs (range 1,5–3,5). No statistical difference in the purging efficacy was found when 3, 4 or 5 MoAbs against B-cells antigens were used. However, a tumor specific signal could be detected in the purged harvest of all patients, when the highly sensitive ASO-PCR approach was used. Furthermore, we found a direct correlation between the amount of remaining monoclonal cells after negative selection and the event free survival of myeloma patients. 10/15 patients with a median of 20 × 103 monoclonal cells in the purged product relapsed at a median of 1,4 years, whereas only 6/24 patients with an oligoclonal pattern including a low number of remaining monoclonal cells relapsed at a median of 2,2 years. The event free survival (EFS) was statistically different between the two groups (p = 0,014).

The Demonstration of Human Tumors on Nude Mice Using Gadolinium-Labelled Monoclonal Antibodies for Magnetic Resonance Imaging

The authors describe the magnetic resonance imaging (MRI) of a tumor in a nude mouse tumor model by means of an antibody-polylysine (Gd-DTPA) conjugate. The monoclonal antibody, (MAB) RA96, was coupled to a polymeric gadolinium complex after periodate oxidation. This polymer, which consists of a polylysine backbone and complexing DTPA subunits, complexes an average of 65 gadolinium ions. The immunoreactivity of the conjugates was reduced by an average of only 30% compared with the unbound MAB RA96. Biodistribution studies in nude mice with subcutaneously implanted human colon carcinomas (WiDr [specific] and HT29 [control]) revealed a tissue concentration in the specific tumor of 8.72% of the dose applied per gram despite the high molecular weight of the conjugates. This tissue concentration is sufficient to achieve tumor-specific signal enhancement in the WiDr tumor on MRI. The problem of the high doses of protein required for MRI and possible solutions are discussed.

The Demonstration of Human Tumors on Nude Mice Using Gadolinium-Labelled Monoclonal Antibodies for Magnetic Resonance Imaging

Göhr-Rosenthal S, Schmitt-Willich H, Ebert W, Conrad J. The demonstration of human tumors on nude mice using gadolinium-labelled monoclonal antibodies for magnetic resonance imaging. Invest Radiol 1993;28:789-795. rational and objectives. The authors describe the magnetic resonance imaging (MRI) of a tumor in a nude mouse tumor model by means of an antibody-polylysine (Gd-DTPA) conjugate. methods. The monoclonal antibody, (MAB) RA96, was coupled to a polymeric gadolinium complex after periodate oxidation. This polymer, which consists of a polylysine backbone and complexing DTPA subunits, complexes an average of 65 gadolinium ions. results. The immunoreactivity of the conjugates was reduced by an average of only 30% compared with the unbound MAB RA96. Biodistribution studies in nude mice with subcutaneously implanted human colon carcinomas (WiDr [specific] and HT29 [control]) revealed a tissue concentration in the specific tumor of 8.72% of the dose applied per gram despite the high molecular weight of the conjugates. conclusions. This tissue concentration is sufficient to achieve tumor-specific signal enhancement in the WiDr tumor on MRI. The problem of the high doses of protein required for MRI and possible solutions are discussed.