Pathogenesis of XXXX : implications for current therapy and for the development of new therapeutic strategies.

@entity5 @entity1 @entity3 @entity1313
Different @entity5 cell subpopulations coexisting within the same @entity5 exhibit varied susceptibilities to antineoplastic agents. @entity5 cell heterogeneity is now recognized as the principal cause of treatment failure in @entity5 , and is a formidable obstacle to effective therapy and to the development of drug delivery systems for selective targeting of antineoplastic agents to @entity5 cells. Recent insights into the genesis of @entity5 cell heterogeneity during progressive @entity5 growth reveal new complexities that raise challenging questions about the adequacy of certain approaches to the current therapy of @entity3 and impose challenging criteria for the development of improved therapeutic strategies. Many of the experimental approaches used in the search for new antineoplastic agents and targeted drug delivery systems ignore the pathogenesis of @entity3 and the problem of @entity5 cell heterogeneity. The adoption of more relevant assay systems is an urgent priority. These include the greater use of @entity3 models and the increased use of @entity1 @entity5 cells to replace rodent cell systems which have been of limited predictive value in identifying effective anticancer agents. In contrast to current strategies for the development of new antineoplastic drugs which seek to identify agents with activity against a broad range of histologically diverse @entity5 , greater success may be achieved by seeking agents active only against specific cell lineages. Many established @entity1 @entity5 cell lines may not be suitable for this purpose because of extensive phenotypic change produced by prolonged passage ex vivo. Development of histiotype-specific @entity1 @entity5 cell screens will require an extensive research effort to identify target cells that display demonstrable phenotypic relatedness to @entity5 cells in @entity1313 . Major advances in the therapy of @entity3 are considered unlikely in the next few years, and progress will stem from improved use of existing agents in refined combination therapy protocols in which greater attention is given to the duration, frequency, and sequence of therapy with different agents to limit emergence of @entity5 cell variants resistant to one or more antineoplastic agents. Advances in molecular biology offer exciting prospects for the identification of new therapeutic targets in @entity1 @entity5 cells, for the induction of alterations in @entity5 cells that could serve as therapeutic targets, and for the elucidation of the mechanisms responsible for the rapid phenotypic diversification of @entity5 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
