Synergistic antitumor effect of chemotherapy and antisense-mediated ablation of the cell cycle inhibitor p27(KIP-1)

The fraction of noncycling cells found in most tumors represents a major ob stacle for conventional chemotherapy, Here, we show that the cyclin-depende nt kinase inhibitor p27(KIP-1) accumulates to high levels in human tumors g rown in immunodeficient mice. We have developed an antisense phosphorothioa te oligodeoxynucleotide (ODN) that efficiently inhibits the expression of p 27(KIP-1) both in vifro and in vivo. Treatment of cultured tumor cells with this ODN sensitized the cells to all chemotherapeutic drugs tested, includ ing the new kinase inhibitor flavopiridol, Furthermore, striking synergisti c effects of the p27(KIP-1) ODN and flavopiridol vopiridol were observed in vivo with respect to both the induction of apoptotic cell death and the in hibition of tumor growth. Importantly, p27(KIP-1) ODN treatment alone did n ot provoke any detectable tumor enhancement. A mechanistic explanation for these findings might be derived from the observation that p27(KIP-1) ODN tr eatment of cultured tumor cells led to a clear increase in the fraction of S-G(2) cells in the absence of an efficient progression into M phase. These findings may have direct relevance to the development of new approaches fo r the treatment of human cancer.