IMPACT OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P27(KIP1) ON RESISTANCE OF TUMOR-CELLS TO ANTICANCER AGENTS

A low proliferating fraction in solid tumors limits the effectiveness of cell cycle-dependent chemotherapeutic agents. To understand the mol ecular basis of such ''kinetic'' resistance we cultured tumor cells as multicellular spheroids and examined levels of p27(Kip1), a cyclin-de pendent kinase inhibitor known to be upregulated by intercellular cont act in normal cells. When transferred from monolayer to three-dimensio nal culture, a consistent upregulation (up to 15-fold) of p27 protein was observed in a panel of mouse and human carcinoma cell lines. Antis ense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary t umor cell spheroids reduced intercellular adhesion, increased cell pro liferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, a nd restored drug- or radiation-induced cell-cycle perturbations repres sed in spheroid culture. Our results implicate p27 as a regulator of d rug resistance in solid tumors and suggest that tumor-targeted p27 ant agonists may be useful chemosensitizers in conjunction with convention al anticancer therapy.