Innovations in chemotherapy and radiation therapy: Implications and opportunities for the Asia-Pacific Rim

New cases of invasive cancer in the United States occur among nearly 1.5 million people annually. In 2007, more than 1,500 people died per day with this diagnosis. Cancer is responsible for nearly one in every four deaths reported in the country. Enormous amounts of money and research have been, and are being spent, in an attempt to improve these numbers. While prevention and early detection remain the key to long-term success, treatment in the neo-adjuvant, adjuvant and metastatic settings still centre around two main treatment modalities – radiation therapy and chemotherapy. This article will review the advances that have been made in both areas that are making these treatments more precise and convenient, as well as less toxic, for the patient. In the field of radiation therapy this involves the development of new therapy planning and delivery systems, such as intensity-modulated radiation therapy (IMRT), and positron emission and computed tomography, PET-CT. Chemotherapy has also evolved with the development of targeted chemotherapy for the treatment of specific malignancies as well as improved supportive care agents which allow for the administration of dose-dense chemotherapy when appropriate

Human Vav1 Expression in Hematopoietic and Cancer Cell Lines Is Regulated by c-Myb and by CpG Methylation

Vav1 is a signal transducer protein that functions as a guanine nucleotide exchange factor for the Rho/Rac GTPases in the hematopoietic system where it is exclusively expressed. Recently, Vav1 was shown to be involved in several human malignancies including neuroblastoma, lung cancer, and pancreatic ductal adenocarcinoma (PDA). Although some factors that affect vav1 expression are known, neither the physiological nor pathological regulation of vav1 expression is completely understood. We demonstrate herein that mutations in putative transcription factor binding sites at the vav1 promoter affect its transcription in cells of different histological origin. Among these sites is a consensus site for c-Myb, a hematopoietic-specific transcription factor that is also found in Vav1-expressing lung cancer cell lines. Depletion of c-Myb using siRNA led to a dramatic reduction in vav1 expression in these cells. Consistent with this, co-transfection of c-Myb activated transcription of a vav1 promoter-luciferase reporter gene construct in lung cancer cells devoid of Vav1 expression. Together, these results indicate that c-Myb is involved in vav1 expression in lung cancer cells. We also explored the methylation status of the vav1 promoter. Bisulfite sequencing revealed that the vav1 promoter was completely unmethylated in human lymphocytes, but methylated to various degrees in tissues that do not normally express vav1. The vav1 promoter does not contain CpG islands in proximity to the transcription start site; however, we demonstrated that methylation of a CpG dinucleotide at a consensus Sp1 binding site in the vav1 promoter interferes with protein binding in vitro. Our data identify two regulatory mechanisms for vav1 expression: binding of c-Myb and CpG methylation of 5′ regulatory sequences. Mutation of other putative transcription factor binding sites suggests that additional factors regulate vav1 expression as well