BRYOSTATIN-1 DOWN-REGULATES MDR1 AND POTENTIATES VINCRISTINE CYTOTOXICITY IN DIFFUSE LARGE-CELL LYMPHOMA XENOGRAFTS

The down-regulation of multidrug resistance (mdr1) gene expression as detected by competitive reverse transcription-PCR and the antitumor ac tivity of bryostatin 1 (Bryo1) are investigated in a newly established cell line from a patient with relapsed diffuse large cell lymphoma (D LCL), The cell line (WSU-DLCL2) grows in liquid culture and forms s.c. tumors in mice with severe combined immune deficiency. WSU-DLCL2 is a mature B-cell line (IgG lambda) that is negative for EBV nuclear anti gen, expresses the multidrug resistance phenotype, and has t(14;18)(q3 2;q21) plus other chromosomal aberrations, Exposure of the WSU-DLCL2 c ells to Bryo1 in culture reversed the multidrug resistance phenotype w ithin 24 h, A functional assay revealed a 3-fold increase in [H-3]vinc ristine accumulation in Bryo1-treated cells compared with control. Vin cristine (VCR), doxorubicin, Bryo1, and 1-beta-D-arabinofuranosylcytos ine showed no clinically significant activity when given alone to WSU- DLCL2-bearing severe combined immune deficiency mice, However, when gi ven 24 h before each cytotoxic agent, Bryo1 substantially increased th e antitumor activity of VCR but not 1-beta-D-arabinofuranosylcytosine. There was a statistically significant (P < 0.001) decrease in the exp ression of beta-glycoprotein in WSU-DLCL2 tumors taken from Bryo1-trea ted animals compared vith untreated controls. In vivo, a competitive r everse transcription-PCR assay revealed decreased mdr1 RNA expression 24 h after Bryo1 treatment. These findings taken together indicate tha t Bryo1-induced down-regulation of mdr1 might be one mechanism by whic h Bryol potentiates VCR activity. The sequential use of both agents re sulted in clinically significant antitumor activity in this lymphoma m odel.