ADENOVIRUS-MEDIATED GENE-TRANSFER OF WILD-TYPE P53 RESULTS IN MELANOMA CELL APOPTOSIS IN-VITRO AND IN-VIVO

Gene transfer techniques may provide efficient treatment for a variety of malignant neoplasms. A replication-deficient adenovirus (Ad) vecto r 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 A dCMV.p53 was also below that of AdCMV.NLS beta gal-infected and uninfe cted controls. DNA laddering using agarose gel electrophoresis and in site labeling of DNA fragmentation (TUNEL) showed that AdCMV.p53-infec ted murine and human melanoma cells underwent apoptosis. Nude mice inj ected s.c. either with B16-G3.26 cells or with SK-MEL-24 cells develop ed localized tumors. These tumors were subsequently infiltrated with e ither AdCMV.p53, AdCMV.NLS beta gal or saline alone. One week after in fection, 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. Thu s, Ad-mediated wildtype p53 overexpression resulted in melanoma cell a poptosis and inhibition of melanoma growth in vitro and in vivo. These gene therapy approaches may be useful in targeting rapidly growing, m alignant melanomas in a clinical setting. (C) 1995 Wiley-Liss, Inc.