Synergistic antitumor effect of chemotherapy and antisense-mediated ablation of the cell cycle inhibitor p27KIP-1.
The fraction of noncycling cells found in most tumors represents a major obstacle for conventional chemotherapy. Here, we show that the cyclin-dependent kinase inhibitor p27KIP-1 accumulates to high levels in human tumors grown in immunodeficient mice. We have developed an antisense phosphorothioate oligodeoxynucleotide (ODN) that efficiently inhibits the expression of p27KIP-1 both in vitro and in vivo. Treatment of cultured tumor cells with this ODN sensitized the cells to all chemotherapeutic drugs tested, including the new kinase inhibitor flavopiridol. Furthermore, striking synergistic effects of the p27KIP-1 ODN and flavopiridol were observed in vivo with respect to both the induction of apoptotic cell death and the inhibition of tumor growth. Importantly, p27KIP-1 ODN treatment alone did not provoke any detectable tumor enhancement. A mechanistic explanation for these findings might be derived from the observation that p27 ODN treatment of cultured tumor cells led to a clear increase in the fraction of S-G2 cells in the absence of an efficient progression into M phase. These findings may have direct relevance to the development of new approaches for the treatment of human cancer.
Achenbach
T V
TV
Institute of Molecular Biology and Tumor Research (IMT), Philipps University, Marburg, Germany.
Müller
R
R
Slater
E P
EP
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008938:Mitosis / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013873:Thionucleotides / Q000235:genetics / Q000494:pharmacology; D014162:Transfection; D025521:Tumor Suppressor Proteins; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D005419:Flavonoids; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D010880:Piperidines; D013873:Thionucleotides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C077990:alvocidib; D018844:Cyclin-Dependent Kinases