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Heterogeneous Response to Differentiation Induction in Different Clonal Subpopulations of a Rat Rhabdomyosarcoma Cell Line (BA-HAN-1)¹

Departments of Pathology [C. D. G., H. E. G., R. E., U. R.], Internal Medicine [H. M., C. L.], and Biochemistry [H. K. B.], Johannes Gutenberg University of Mainz, D-6500 Mainz, Federal Republic of Germany

Three clonal subpopulations (A, B, C) isolated from the same rhabdomyosarcoma of the rat were tested and compared for their susceptibility to differentiation induction using retinoic acid (RA), dimethylformamide (DMF), and N-monomethylformamide (NMF). These subpopulations differ in that a block to spontaneous differentiation is imposed at different stages which are characteristic for each subpopulation. Whereas tumor cell proliferation was significantly inhibited (P < 0.001) in all three subpopulations, the effects of RA, DMF, and NMF on tumor cell differentiation were strikingly heterogeneous. The response was most marked in subpopulation C, as evidenced by a significant increase in the number of terminally differentiated myotube-like giant cells (P < 0.001) and in biochemical differentiation, as indicated by the creatine kinase activity (P < 0.05). Between 5% (DMF and NMF) and 30% (RA) of the mononuclear cells in subpopulation C exhibited thick and thin myofilaments, which were never observed in the mononuclear cells of the control. In contrast, subpopulation A and B responded to RA, DMF, and NMF quite heterogeneously with an increase in biochemical differentiation, whereas terminally differentiated myotube-like giant cells were never observed. These results demonstrate that the therapeutic potential of differentiation induction in malignant tumors may be impaired by tumor heterogeneity.

¹ This work supported by the Gesellschaft der Gönner und Förderer der Grundlagenforschung des Krebses.

² To whom requests for reprints should be addressed, at, Department of Pathology, Johannes Gutenberg University of Mainz, D-6500 Mainz, Federal Republic of Germany.

Received 10/24/88. Revised 4/17/89. Revised 9/18/89. Accepted 9/21/89.