Gastric cancer is one of the most common cancers and most frequent causes of cancer-related deaths in the world. The overall survival rate is 15-20%. Although the incidence is declining, its prognosis remains poor. The etiological factors and pathogenesis of gastric cancer are not yet fully understood. The integrated research in molecular pathology clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of development and progression of gastric cancer. Although epidemiological evidences indicate that environmental factors play a major role in the carcinogenesis, the role of immunological, genetic and immunogenetic factors are thought to contribute to etiopathogenesis of gastric carcinoma. In addition to better understanding of pathogenesis of gastric cancer, the incidence, diagnostic studies and the therapeutic options have also undergone important changes in the last decade. There is ongoing debate regarding the role of adjuvant treatment. In advanced disease, palliation of symptoms, rather than cure, is the primary goal of patient management. Several combination therapies have been developed and have been examined in phase III trials; however, in most cases, they have failed to demonstrate a survival advantage over the reference arm. This review summarizes the newer concepts of molecular biology on gastric carcinogenesis and the new important recommendations for the management of patient with gastric carcinoma.
Incidence rates of gastric cancer in Malaysia has declined by 48% among males and 31% among females in the latest reporting period of 13 years. Malays used to have age-standardized-rates only a fifth of those in Chinese and Indians, but the incidence among them is slightly rising even as the rates drop in the other races. Besides ethnicity, a low level of education, high intake of salted fish and vegetables, H pylori infection and smoking are risk factors. Consumption of fresh fruit and vegetable is protective. Variation in the strains of H pylori infection affect gastric cancer risk, with hspEAsia isolates among Chinese appearing linked to a high incidence than with hpAsia2 or hpEurope strains among Indians and Malays. It was reported in the 1980s that only about 3% of patients presented with early gastric cancer, but more encouraging rates reaching 27% with Stage 1 and 2 disease have been reported in the twenty-first century from leading centres. More tumours occur in the distal stomach except in Kelantan, where the incidence is low and main site is the cardia. Prompt endoscopy is advocated and open access, with direct referrals, to such services using a weighted scoring system should be more utilized. In view of the high rate of late disease laparoscopic staging unnecessary laparotomy needs to be avoided. Late presentation of gastric cancer however, is still predominant and the mortality to incidence ratio is relatively high. Besides seeking to reduce risk factors and achieve early detection, implementation of improved care for patients with late disease must be promoted in Malaysia.
Epigenetic inhibitors have shown anticancer effects. Combination chemotherapy with epigenetic inhibitors has shown high effectiveness in gastric cancer clinical trials, but severe side effect and local progression are the causes of treatment failure. Therefore, we sought to develop an acidity-sensitive drug delivery system to release drugs locally to diminish unfavorable outcome of gastric cancer. In this study, we showed that, as compared with single agents, combination treatment with the demethylating agent 5'-aza-2'-deoxycytidine and HDAC inhibitors Trichostatin A or LBH589 decreased cell survival, blocked cell cycle by reducing number of S-phase cells and expression of cyclins, increased cell apoptosis by inducing expression of Bim and cleaved Caspase 3, and reexpressed tumor suppressor genes more effectively in MGCC3I cells. As a carrier, reconstituted apolipoprotein B lipoparticles (rABLs) could release drugs in acidic environments. Orally administrated embedded drugs not only showed inhibitory effects on gastric tumor growth in a syngeneic orthotopic mouse model, but also reduced the hepatic and renal toxicity. In conclusion, we have established rABL-based nanoparticles embedded epigenetic inhibitors for local treatment of gastric cancer, which have good therapeutic effects but do not cause severe side effects.