Abstract
Abstract Cancer has been the leading cause of death in Taiwan since 1982. Among which brain tumors are the leading factors of cancer deaths in the population of 15-35 years old. Traditionally therapeutic strategies for unresectable brain tumors were radiation therapy and chemotherapy. However, most of these strategies are not satisfactorily successful. Meanwhile, due to the progressive aging of our society, there is increasing incidence of brain tumors and degenerative diseases. The development of new generation brain targeting drugs for brain tumors and degenerative diseases is very important. Traditional chemotherapeutic strategies for cancer are developed mainly based on DNA damaging mechanism. However, recently scientists found that RNA damage caused by ribonucleases (RNases) could be an important alternative. Among these, the secretory human eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) have been shown to be effective for some cancers and are classified as antitumor RNases. In the study, recombinant DNA technology was applied to produce the two antitumor RNases, i.e. recombinant mature human eosinophil cationic protein (rECP) and recombinant mature human eosinophil-derived neurotoxin (rEDN). The cell entry ability and potential roles of these human eosinophil Rnases in the therapy of brain tumor and other diseases were investigated. It was found that both rECP and rEDN internalized the columnar epithelium of respiratory and intestinal tracts efficiently. Further study proved that such cell entry effect occurred very likely through the binding with some special type of membrane bound heparan sulfate receptors on the cell surface. Although neither rECP nor rEDN could directly penetrate through blood brain barrier (BBB), once they were forcefully injected into the subarachnoid spaces both showed highly selective cell binding and cell entry effect to the pyramidal neurons and Purkinje neurons. Further modification of the rECP and rEDN molecules by genetic engineering techniques such as chimeric or site-directed mutagenesis can be carried out in the future to improve the selectivity and decrease possible side effects of the two recombinant RNases, the modified eosinophil RNases can be further used as potential chemotherapeutic agents or even as molecular Trojan horses for the therapy of brain tumors, brain degenerative diseases, and other special diseases related to respiratory and digestive organs.