PLEIOTROPIC OVER-EXPRESSION OF MULTIDRUG-RESISTANCE-RELATED GENES IS CORRELATED TO MYCN AND MAX MESSENGER-RNA ACCUMULATION DURING TUMOR PROGRESSION IN THE IGR-N-91 HUMAN NEUROBLASTOMA MODEL

An experimental model of advanced human neuroblastoma, IGR-N-91, which is able to disseminate in the nude mouse, has been described. The pre sent study was designed to ascertain which cell population from the IG R-N-91 primary tumour actually disseminates throughout the animals, In s.c. IGR-N-91 tumour xenografts, 3 areas, called pearly, vascularized and haemorrhagic, depending on the presence of blood vessels and haem orrhagic suffusions, were consistently observed and independently rese cted. Molecular analysis of tumour materials revealed a significant in crease in MYCN and max gene transcript revels in the haemorrhagic area , as compared with the pearly and vascularized areas. Given the growth kinetics observed both in vitro and in vivo, and the DNA flow-cytomet ry profiles of tumour cells obtained from the haemorrhagic area, this transcriptional increase did not appear to be associated with enhanced proliferation. In this area of the tumours, multidrug-resistance-rela ted genes, re., MDRI, MRP, GST-pi; and topoisomerase II alpha were act ivated concomitantly with MYCN and max genes. The same observations we re made, except for the topoisomerose-II alpha gene, when sub-lines de rived from metastases were compared with that derived from the primary tumour. These data demonstrate that over-expression of several genes determining the multidrug-resistance phenotype precedes the metastatic spread of ICR-N-91 NE tumour cells in the nude mouse. Data also sugge st that the cell sub-population exhibiting this pleiotropic over-expre ssion within the primary tumour undergoes selection during metastatic dissemination. (C) 1997 Wiley-Liss, Inc.