New insights into the kinetic resistance to anticancer agents

Kinetic resistance plays a major role in the failure of chemotherapy toward s many solid tumors. Kinetic resistance to cytotoxic drugs can be reproduce d in vitro by growing the cells as multicellular spheroids (Multicellular R esistance) or as hyperconfluent cultures (Confluence-Dependent Resistance). Recent findings on the cell cycle regulation have permitted a better under standing why cancer cells which arrest in long quiescent phases are poorly sensitive to cell-cycle specific anticancer drugs. Two cyclin-dependent kin ase inhibitors (CDKI) seem particularly involved in the cell cycle arrest a t the G1 to S transition checkpoint: the p53-dependent p21(cip1) protein wh ich is activated by DNA damage and the p27(kip1) which is a mediator of the contact inhibition signal. Cell quiescence could alter drug-induced apopto sis which is partly dependent on an active progression in the cell cycle an d which is facilitated by overexpression of oncogenes such as c-Myc or cycl ins. Investigations are yet necessary to determine the influence of the cel l cycle on the balance between antagonizing (bcl-2, bcl-X-L...) or stimulat ing (Bax, Bcl-X-S, Fas...) factors in chemotherapy-induced apoptosis. Quies cent cells could also be protected from toxic agents by an enhanced express ion of stress proteins, such as HSP27 which is induced by confluence. New s trategies are required to circumvent kinetic resistance of solid tumors: ad equate choice of anticancer agents whose activity is not altered by quiesce nce (radiation, cisplatin), recruitment from G1 to S/G2 phases by cell pret reatment with alkylating drugs or attenuation of CDKI activity by specific inhibitors.