Induction and reversal of cell adhesion-dependent multicellular drug resistance in solid breast tumors.

ABSTRACT

Although there are a number of chemotherapeutic drugs available for the treatment of breast cancer, eg. adriamycin, cyclophosphamide and taxol, their effectiveness is severely limited by expression of intrinsic resistance in some patients and by acquired resistance in others. There is thus an urgent need to develop innovative methods to try and make these drugs more effective than is currently the case. One such method is to combine them with novel "chemosensitizers", i.e., drugs which themselves lack anti-tumor cytotoxic properties but which will increase the efficacy of those which do. In this regard we hae been studying the hypothesis that the resistance of solid tumors, including breast cancer, can be expressed at the prototissue/multicellular level, and that this "multicellular resistance" can be minimized or reversed by the appropriate use of so-called "anti-adhesive" agents. RESULTS/BACKGROUND: It is well known that monolayer cultures of tumor cells-including murine breast cancer-are generally much more intrinsically chemosensitive than the same cells grown as solid tumors in vivo. However, the relative resistance of solid tumors can often be recapitulated in tissue culture simply by growth of the tumor cells as three dimensional multicellular spheroids. There are cases where this is also true with respect to acquired drug resistance. This "multicellular resistance" could be due to such factors as insufficient drug penetration, a reduced growth fraction, or a decreased sensitivity to drug induced apoptosis mediated by cell-cell interaction survival signals. Can such multicellular resistance mechanisms in solid tumors be reversed? With respect to this question, we have recently found that the relative intrinsic resistance of intact murine EMT-6 mouse mammary carcinoma spheroids can be significantly reversed by the anti-adhesive (disaggregating) effects of hyaluronidase. Moreover, this novel method of chemosensitization appears to depend on increased recruitment of disaggregated cells into the cycling pool, thus rendering them more sensitive to a cell cycle dependent drug such as cyclophosphamide. The reduced growth fraction observed in spheroids appears to be due to a marked cell contact-dependent upregulation of the cyclin dependent kinase inhibitor, p27Kipl. FUTURE OBJECTIVE: The overall goal of our current and future research is to determine whether solid tumors, including human breast cancer, express intrinsic or acquired resistance at the multicellular level to such drugs as taxol or cyclophosphamide, and if so, determine whether it can be reversed by the chemosensitizing effect of anti-adhesive agents. This will require a search for effective anti-adhesive agents for human cancers as hyaluronidase has not been found to possess anti-adhesive function against such tumors to date. In addition, the counter-intuitive and innovative idea of downregulating p27kipl in human breast cancers as a means of cytotoxic drug chemosensitization is also being evaluated.