Retinoic-acid-resistant neuroblastoma cell lines show altered MYC regulation and high sensitivity to fenretinide

Background. High-dose, pulse-13-cis-retinoic acid (13-cis-RA) given after i ntensive cytotoxic therapy improves event-free survival for high-risk neuro blastoma (NB), but more than 50% of patients have tumor recurrence. Procedu re. We conducted multistep selection for resistance to all-trans-retinoic a cid (ATRA) in NE cell lines with (SMS-KCNR and LA-N-5) or without (SMS-LHN) MYCN genomic amplification. Results. After 12 exposures to 10 muM ATRA, th e two MYCN-amplified cell lines (KCNR 12X RR and LA-N-5 12X RR) showed part ial resistance to the cytostatic/difierentiation effects of ATRA; complete resistance was seen in LHN 12X RR. ATRA-selected cells showed general RA re sistance (cross-resistance to 13-cis-RA). Transient (KCNR 12X RR, LA-N-5 12 X RR) or sustained (LHN 12X RR) novel overexpression of c-myc was associate d with RA resistance. RA-insensitive overexpression of MYCN by transduction in SMS-LHN also conferred RA resistance. Both parental and RA-resistant li nes showed 2-4 logs of cell kill in response to N-(4-hydroxyphenyl)retinami de (4-HPR, fenretinide). Compared to parental lines, 4-HPR achieved 1-3 log greater cell kills in RA-resistant LHN 12X RR, LA-N-5 12X RR, KCNR 12X RR, and MYCN-transduced SMS-LHN or SK-N-RA. NE cell lines (n = 26) from 21 dif ferent patients showed that 16 of 26 (62%) were sensitive to 4-HPR (LC90 < 10 <mu>M), including lines established at relapse after myeloablative and/o r 13-cis-RA therapy. Conclusion. Thus, RA-resistant NE cell lines can be se nsitive (and in some cases collaterally hypersensitive) to 4-HPR. (C) 2000 Wiley-Liss, Inc.