Proc. Natl. Acad. Sci. USA: Vol. 98, No. 18, 1033210337, August 28, 2001
A combinatorial approach for selectively inducing programmed
cell death in human pancreatic cancer cells
Zao-zhong Su, Irina V. Lebedeva, Rahul V. Gopalkrishnan, Neil I. Goldstein, C. A. Stein,
John C. Reed, Paul Dent, and Paul B. Fisher
Departments of Urology, Pathology, Medicine, and Neurosurgery, Herbert Irving
Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York,
NY 10032; DGI Biotechnologies, Edison, NJ 08818; Burnham Institute, La Jolla, CA 92037; and
Department of Radiation Oncology, Medical College of Virginia, Richmond, VA 23298
Z.-z.S. and I.V.L. contributed equally to this work.
Communicated by Allan H. Conney, Rutgers, State University of New Jersey New Brunswick,
Piscataway, NJ June 21, 2001 (received for review December 11, 2000)
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. |
