Induction of Drug Resistance in Human Rhabdomyosarcoma Cell Lines is Associated with Increased Maturation: Possible Explanation for Differentiation in Recurrences?

Abstract

In rhabdomyosarcoma (RMS) of childhood and adolescence very little is known about interactions of cytotoxic drugs and tumor cells. In recurrent RMS the tumor cells are often more mature than in the primary tumor. The biological properties of these cells are still a subject of controversy. We investigated two human (RD2 and TE 671) cell lines by cultivating them with doxorubicin, cisplatinum, and etoposide. Degree of differentiation and proliferation rate were estimated morphologically and by means of immunohistochemistry and a mono-layer proliferation assay. Both morphological and immunohistochemical maturation was measurable in most resistant cell lines. An increase in myosin expression was most marked in the etoposide- and doxorubicin-resistant RD cell lines. The proliferation rate was decreased in almost all resistant cell lines. Nevertheless, the resistant cell lines tolerated high-dose levels of cytotoxic drugs at a higher proliferation rate than parental cell lines cultivated under similar conditions. The maturation seen in some recurrent tumors of RMS can be simulated in vitro by cultivating cell lines with cytotoxic drugs at sublethal doses. Interestingly, the resistance-associated induced maturation was not accompanied by p170 expression. After comparing these in vitro results with the maturation seen in RMS specimens after chemotherapy, we conclude that chemotherapy-induced differentiation in vivo might be a morphological sign of chemoresistance.