Adenovirus‐mediated gene transfer of wild‐type p53 results in melanoma cell apoptosis in vitro and in vivo

Abstract

Gene transfer techniques may provide efficient treatment for a variety of malignant neoplasms. A replication-deficient adenovirus (Ad) vector which carries the cDNA for wild-type p53 (AdCMV.p53) was tested for its in vitro and in vivo effects on the growth of murine melanoma cell line B16-G3.26 and human melanoma cell line SK-MEL-24. The growth of B16-G3.26 cells infected with AdCMV.p53 was inhibited when compared to the uninfected cells or cells infected with the control vector AdCMV.NLS beta gal. Similarly, the growth of SK-MEL-24 cells infected with AdCMV.p53 was also below that of AdCMV.NLS beta gal-infected and uninfected controls. DNA laddering using agarose gel electrophoresis and in situ labeling of DNA fragmentation (TUNEL) showed that AdCMV.p53-infected murine and human melanoma cells underwent apoptosis. Nude mice injected s.c. either with B16-G3.26 cells or with SK-MEL-24 cells developed localized tumors. These tumors were subsequently infiltrated with either AdCMV.p53, AdCMV.NLS beta gal or saline alone. One week after infection, B16-G3.26 tumors exposed to AdCMV.p53 were 2.5 times smaller than control tumors and exhibited DNA fragmentation. A similar growth-inhibitory effect of AdCMV.p53 was observed with SK-MEL-24 tumors. Thus, Ad-mediated wild-type p53 overexpression resulted in melanoma cell apoptosis and inhibition of melanoma growth in vitro and in vivo. These gene therapy approaches may be useful in targeting rapidly growing, malignant melanomas in a clinical setting.

The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells

“…For comparison, the e ects of Ad.vec (control adenovirus lacking the mda-7 gene insert) and adenoviruses expressing growth suppressing/apoptosis inducing genes, wild-type p53 (Ad.p53) or the cell cycle kinase inhibitor p21 (Ad.p21) (CIP-1, mda-6, SDI-1, WAF-1) el Deiry et al, 1993;Harper et al, 1993;Noda et al, 1994;Jiang et al, 1995b,c) were determined. Previous studies demonstrate that Ad.p53 induces growth suppression and apoptosis in murine (B16) and human (SK-MEL-24) melanoma cells, both in vitro and in vivo in nude mice (Cirielli et al, 1995). Similarly, infection of UM-316 human melanoma cells with an adenoviral vector expressing p21 (mda-6) results in induction of a more di erentiated phenotype and growth is suppressed both in vitro and in vivo in nude mice .…”

Stable reintroduction of wild-type P53 (MTmp53ts) causes the induction of apoptosis and neuroendocrine-like differentiation in human ductal pancreatic carcinoma cells

“…Apoptosis induced by stable expression of wildtype p53 has been demonstrated in mouse myeloid leukemia cells (Yonish-Rouach et al, 1991, 1993, mouse T-cell lymphomas (Clarke et al, 1993), murine and human melanomas (Cirielli et al, 1995), human lung cancer spheroids (Fujiwara et al, 1993), head and neck squamous cell carcinoma (Liu et al, 1994), and colon carcinomas (Shaw et al, 1992). These wild-type p53 induced e ects are often cell-type dependent, and in¯uenced by the di erentiation state of the tumor cells.…”

Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence

“…Adenovirally mediated p53 tumor-suppressor gene therapy has been shown to be efficacious against colorectal cancer, 2 prostate cancer, 3,4 breast cancer, 5,6 cervical cancer, 7 ovarian carcinoma, 8 and melanoma. 9 Recently, a retrovirus (LXSN) expressing the BRCA1 tumor-suppressor gene was used in a phase I human clinical trial for advanced prostate cancer. 10 The identification of key tumor-suppressor genes that may successfully inhibit or destroy prostate cancer cells is paramount.…”