A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells.

Abstract

Pancreatic cancer is an extremely aggressive neoplasm whose incidence equals its death rate. Despite intensive analysis, the genetic changes that mediate pancreatic cancer development and effective therapies for diminishing the morbidity associated with this disease remain unresolved. Through subtraction hybridization, we have identified a gene associated with induction of irreversible growth arrest, cancer reversion, and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). Ectopic expression of mda-7 when using a recombinant adenovirus, Ad.mda-7, results in growth suppression and apoptosis in a broad spectrum of human cancers with diverse genetic defects, without exerting deleterious effects in normal human epithelial or fibroblast cells. Despite the apparently ubiquitous antitumor effects of mda-7, pancreatic carcinoma cells are remarkably refractory to Ad.mda-7 induced growth suppression and apoptosis. In contrast, the combination of Ad.mda-7 with antisense phosphorothioate oligonucleotides, which target the K-ras oncogene (a gene that is mutated in 85 to 95% of pancreatic carcinomas), induces a dramatic suppression in growth and a decrease in cell viability by induction of apoptosis. In mutant K-ras pancreatic carcinoma cells, programmed cell death correlates with expression and an increase, respectively, in MDA-7 and BAX proteins and increases in the ratio of BAX to BCL-2 proteins. Moreover, transfection of mutant K-ras pancreatic carcinoma cells with an antisense K-ras expression vector and infection with Ad.mda-7 inhibits colony formation in vitro and tumorigenesis in vivo in nude mice. These intriguing observations demonstrate that a combinatorial approach, consisting of a cancer-specific apoptosis-inducing gene and an oncogene inactivation strategy, may provide the foundation for developing an effective therapy for pancreatic cancer.

• Authors: Z Su, I V Lebedeva, R V Gopalkrishnan, N I Goldstein, C A Stein, J C Reed, P Dent, P B Fisher
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 18 Pg. 10332-7 (Aug 28 2001) ISSN: 0027-8424 [Print] United States
• PMID: 11526239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BAX protein, human
• Bax protein, mouse
• Growth Substances
• Interleukins
• Oligodeoxyribonucleotides, Antisense
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• interleukin-24

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis (genetics)
• Base Sequence
• Genes, Tumor Suppressor
• Genes, ras
• Genetic Therapy
• Growth Substances (genetics)
• Humans
• Interleukins
• Mice
• Mice, Nude
• Mutation
• Oligodeoxyribonucleotides, Antisense (genetics, therapeutic use)
• Pancreatic Neoplasms (genetics, pathology, therapy)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Tumor Cells, Cultured
• bcl-2-Associated X Protein