Apoptosis is a key regulator or tissue homeostasis. Death ligands and death receptors of the tumor necrosis factor (TNF) family play crucial roles in mediating apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) is unique amongst death ligands in that it uniquely induces apoptosis in transformed cells, but not normal cells. Indeed, TRAIL is being developed as an anticancer therapy. However, many malignant tumors are resistant to apoptosis induction by TRAIL. Understanding the mechanism of resistance to TRAIL-mediated apoptosis will not only provide insight regarding transduction of the death signal, but will also be essential for designing strategies to overcome resistance to TRAIL for clinical applicatons. In this review, we focus on the apoptosis signaling pathways stimulated by TRAIL, and summarize recent clues regarding TRAIL physiology.
Monoclonal antibodies have already established a secure position as a very promising strategy for anti-tumor therapeutics. High specificity and high affinity are attractive characteristics of antibodies which make them suitable for clinical applications. Advances in genetic engineering have enabled to generate recombinant antibodies which circumvent the problems of using murine antibodies in human therapy. Immunological effects, specific delivery of antibody conjugated-toxins to target cancer cells, and direct effects through receptor engagement by antibodies have been exploited as mechanisms which generate anti-tumor activity. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and can induce apoptosis in a wide variety of human cancer cell lines via its interactions with TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), but does not affect most normal human cells. From the clinical viewpoint, the use of a recombinant soluble form of TRAIL and agonistic antibodies specific for TRAIL-R1 and TRAIL-R2 as anti-tumor agents have been investigated. These promising therapeutic agents are now undergoing clinical investigations. In this review, we summarize the characteristics of recently developed anti-tumor therapeutic antibodies and discuss the current status of therapeutic approaches targeting TRAIL receptors, both by application of TRAIL and by treatment with agonistic monoclonal antibodies. Both these strategies show great promise as therapeutic agents for treatment of cancer patients.
The majority of cancer cells are thought to have accumulated the necessary mutations for oncogenesis as a result of disrupting the cell cycle G1 checkpoint, leading to the replication of damaged DNA. In fact, all of the historical suspects of oncogenesis - mutagens, viruses and heredity - have been shown to impair G1 checkpoint function. As a result, more than half of all human cancer cells with impaired G1 checkpoint function rely on the G2 checkpoint to survive against the DNA damage which most cytotoxic cancer treatments cause. The G2 cell cycle checkpoint is not used heavily by normal cells, which makes a cell cycle G2 checkpoint abrogation strategy attractive for the battle against cancer. Early studies focused on non-specific G2 checkpoint abrogators, including; caffeine, pentoxifylline, fostriecin, okadaic acid and UCN-01. The search for more selective G2 checkpoint abrogators has been ongoing since the central molecular mechanism of the G2 checkpoint was revealed in 1997. So far most of the candidate compounds target the CHK1 and/or CHK2 proteins. Among the more selective G2 abrogators, the first to go into human clinical trials since UCN-01 will be the synthetic peptide CBP501.
RNA interference (RNAi) can be applied to human cancer cells by using small interfering RNAs (siRNAs) for inhibition of activated oncogenes' expression with the amelioration of several malignant phenotypes such as uncontrolled cell growth, resistance to apoptosis or invasive ability. siRNAs with high specificity to active oncogenes (e.g. missense mutation, gene rearrangement or over-expression) could be alternatives for molecular target drugs although several issues such as in vivo siRNA delivery methods, off-target effects, interferon responses require to be solved.
Extensive axillary lymph node involvement in breast cancer patients implies poor prognosis, and is an indication for chest wall irradiation. Patients presenting with small tumors and a negative axillary status clinically, are expected to have a good prognosis. A treatment strategy chosen based on such assumption might prove to be sub-optimal in case of extensive axillary involvement. Our goal was to determine the incidence of extensive axillary involvement of four nodes or more in patients with T1-T2 tumors, and to evaluate the potential consequences of pre-operatively underestimated extensive axillary disease. We reviewed the charts of patients who underwent sentinel lymph node biopsy for primary T1-T2 invasive breast cancer, with a negative pre-operative axillary assessment. Tumor size, histology, and rates and extent of axillary involvement were noted. Of 239 patients, 71 (29.7%) had involved axillary nodes. Fifty-eight of these 71 patients had 1-3 involved nodes and the remaining 13 patients had 4 to 18 involved nodes. Of 168 patients with T1 tumors, 3 (1.8%) had 4 to14 metastatic nodes, and of 71 patients with T2 tumors, 10 (14%) had 4-18 metastatic nodes. A small percentage of patients undergoing sentinel lymph node biopsy have advanced loco-regional disease due to significant axillary nodal involvement. This should be taken into consideration when planning immediate reconstruction. Prophylactic measures such as contra-lateral mastectomy in patients at high risk for a second primary tumor, when considered, might better be deferred until the final pathology report is available. This is so patients with poor prognosis, evident by extensive lymph node involvement not known pre-operatively, do not undergo un-necessary prophylactic surgery such as contra-lateral mastectomy they will probably not benefit from.
Aims The purpose of this study was to confirm whether the endoscopical mucosal resection for early gastric replace to the traditional gastrectomy on the view point of long term patients' outcomes. Methods Among consecutive series of 1298 patients with early gastric cancer (EGC), a total of 214 cases with EGC endoscopically resected from May 1989 and December 2001 were included in the study. Among them 26 patients (11.6%) underwent additional EMR followed by surgery, because of the residual cancer, and they received 17 distal gastrectomy (DG), 7 proximal gastrectomy (PG), and 2 total gastrectomy (TG). The rest 188 patients were received EMR only and were followed without gastrectomy. Eight hundred fifteen patients received DG, 135 PG, 107 TG, 11 wedge-resection of the stomach and 5 resection of the rest stomach between July 1975 and December 2001. Between July 1975 and April 1989, 369 patients received distal gastrectomy (DG), 30 proximal gastrectomy (PG), 52 total gastrectomy (TG), 2 wedge-resection of the stomach and 2 resection of the rest stomach. Results Ten-year survival rates of patients underwent distal G, PG, TG, wedge-resection, resection of the rest stomach, and EMR were, 81.1%, 70.4%, 52.0%, 42.1%, 0%, and 49.2%, respectively. There were significant differences between DG and EMR (log rank test, p<0.0001). Among mucosal cancer patients 18/500(3.6%), 1/66(1.5%), 1/48(2.1%), and 1/183(0.5%) who received DG, PG, TG, and EMR were disease specific death in this analysis. Among submucosal cancer patients, 14/335(4.2%), 0/76(0%), 5/59(8.5%), and 1/15(6.7%) who received DG, PG, TG, and EMR were disease specific death. Comparing to the patients between receiving EMR alone, and gastrectomy after EMR, and between indicated ERM patients by criteria of the Japanese Gastroenterology Endoscopy Society and no-indicated patients, the former was better outcome than the latter, and also showed to not be better than those with distal gastrectomy. Conclusions The outcome of patients who received EMR were not better than those who received distal gastrectomy, however, it is important to treat with minute and small cancer patients such as early cancer by endoscopy on the view point of patients' QOL. From our results doctors who treat cancer patients by endoscopy, must guide the important of the restriction of diet in cancer patients, which is not correlate to cure cancer, but to patients' good QOL as well as persons without cancer.
Background: The influence of lower body mass index on the survival in cancer patients has not been fully estimated. While, many studies suggest that body mass index were positively associated with an increased risk of cancers of the esophagus, colon, gallbladder, pancreas, breast, endometrium, kidney, and ovary, so the rapid growth in the prevalence of obesity as new threats foretells health problems in years to come. Methods: We assessed preoperative body mass index (BMI) of 2677 patients with malignant and benign diseases who enrolled in the data base for The Japanese Society of strategies of Cancer research and Therapy from May 1975 to February 2004, for evaluating how BMI effect on the outcomes of patients, with examining some parameters. Results: During the period of this study from 1975-, the median BMI increased from 21.6 kg/m2, 21.9 kg/m2, 21.9 kg/m2, and 22.2 kg/m2, to 22.4 kg/m2. Serum gastrrin levels, T-IGR, SA, IAP, and CEA were increased significantly than those in both normal and obesity patients. The 10-year-survival rates (disease specific death) of patients of underweight, normal, overweight, and obese were 38.0 (52.0) %, 58.7 (69.5) %, 68.5 (77.4) %, and 54.3 (62.6) %, respectively. (Fig. 3 left) There were significant differences among these groups. (Underweight vs. normal, overweight, and obese, p<0.001, p<0.001, and p=0.042. normal vs. overweight, p<0.001) Conclusions: We found that underweight as well as obese not but overweight patients were shown poor survival rates, and that underweight group showed older persons with lower acid output, higher gastrinemia, higher serum levels of IAP, sialic acid, and CEA than normal weight and overweight group. These findings of this study suggest that underweight group also alterations in growth factors and acute phase reactants. This needs to be investigated in other samples and populations.
Background: Dendritic cells (DCs) are the strongest antigen presenting cells (APCs). They can present antigen to T lymphocytes in vivo and in vitro, and induce cytotoxic T lymphocyte (CTL) reactions. This study was designed to investigate the immunologic potency and antitumor effecs of tumor vaccine produced by electrofusion between rat osteosarcoma cells and DCs. Methods: DCs obtained from rat bone marrow were propagated in vitro under the condition of rGM-CSF, rIL-4 and rTNF-α and were purified by monoclonal antibody OX62 and magnetic beads. Then the UMR-106 cell line was fused with DCs to produce the tumor vaccine and the specific antitumor effects of the tumor vaccine were observed. Results: A comparison of electrofusion products generated with allogeneic versus syngeneic DCs was conducted. 70% of the rats immunized with allogeneic electrofused cells were typically able to reject tumor challenge and remained tumor-free, while 50% in the syngeneic group. Vaccinated survivors developed long immunological memory. 7 weeks after the second challenge, all the immunized rats survived. The therapeutic potential of this type of approach was suggested by the ability of UMR106-DC electrofusion products to induce tumor rejection in a substantial percentage of hosts (60%) bearing pre-established tumor cells. Interpretations: Treatment with electrofused tumor cells and allogeneic DCs might be capable of inducing a potent antitumor response and could conceivably be applied to a wide range of cancer indications for which tumor-associated antigens have not been identified.