Intractable Cancers: The Many Faces of Multidrug Resistance and the Many Targets it Presents for Therapeutic Attack

Stein W.D.; Bates S.E.; Fojo T.

Abstract

Some types of cancer respond far less favorably to treatment than do others. A quantitative estimate of this intuition can be obtained from the SEER (Surveillance, Epidemiology and End-Results) Cancer Statistics Review. Of particular interest, from a drug resistance perspective, are the five-year survival data for patients presenting with tumors that were diagnosed as “distant”. A good correlation can be found between those numbers and an estimate of treatment successes obtained from a survey of current literature on chemotherapy applied to cancers originating from these various tissues. These two measures, considered together, define “the axis of intractability”, a parameter that characterizes the (possibly) inherent, physiological basis of the tissue-by-tissue intractability of cancers. Exploring the basis of this intractability, it appears that factors other than the classical ABC transporter-based, multidrug resistance systems probably play a major role. An ineffective DNA repair system, coupled to reduced apoptosis, is the basis for the inherent tractability of testicular cancer. For other tissues, important contributions to resistance arise from cell adhesion-mediated drug resistance, which is overcome when cells are released from tissues during anoikis. Making a direct comparison between gene expression in solid tumors and their corresponding cell lines, genes controlling the extracellular matrix and cell-cell communication appear among the genes that are over-expressed in the solid tumors, while genes coding for the protein biosynthesis system are over-expressed in the cell lines. The more tractable cancers are closer to the cell lines in their expression profiles of these sets of genes.

Keywords: drug resistance, Intractable tumors, abc transporters, apoptosis, dna repair, drug distribution, anoikis, cell adhesion