Targeting c-Myb expression in human disease.
c-Myb is a transcription factor employed in the haematopoietic system and gastrointestinal tract to regulate the exquisite balance between cell division, differentiation and survival. In its absence, these tissues either fail to form, or show aberrant biology. Mice lacking a functional c-myb gene die in utero by day 15 of development. When inappropriately expressed, as is common in leukaemia and epithelial cancers of the breast, colon and gastro-oesophagus, c-Myb appears to activate gene targets of key importance to cancer progression and metastasis. These genes include cyclooxygenase-2 (COX-2), Bcl-2, BclX(L) and c-Myc, which influence diverse processes such as angiogenesis, proliferation and apoptosis. The clinical potential for blocking c-Myb expression in malignancies is based upon strong preclinical data and some trial-based evidence. The modest clinical experience to date has been with haematopoietic malignancies, but other disease classes may be amenable to similar interventions. The frontline agents to achieve this are nuclease-resistant oligodeoxynucleotides (ODNs), which are proving to be acceptable therapeutic reagents in terms of tolerable toxicities and delivery. Nevertheless, further effort must be focused on improving their efficacy, eliminating non-specific toxicity and optimising delivery. Optimisation issues aside, it would appear that anti-c-Myb therapies will be used with most success when combined with other agents, some of which will be established cytotoxic and differentiation-inducing drugs. This review will explore the future strategic use of ODNs in vivo, focusing on a wide spectrum of diseases, including several beyond the haematopoietic malignancies, in which c-Myb appears to play a role.
Ramsay
Robert G
RG
Differentiation and Transcription Group, Trescowthick Laboratories, Peter MacCallum Cancer Institute, Victoria, Australia. r.ramsay@pmci.unimelb.edu.au
Barton
Anna L
AL
Gonda
Thomas J
TJ
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D015195:Drug Design; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D020570:Genes, myb / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000737:chemistry / Q000187:drug effects; D012334:RNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D012334:RNA, Neoplasm