Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts

• Published in: Clinical cancer research 1998-05, Vol.4 (5), p.1305-1314
• Main Authors: AL-KATIB, A. M, SMITH, M. R, KAMANDA, W. S, PETTIT, G. R, HAMDAN, M, MOHAMED, A. N, CHELLADURAI, B, MOHAMMAD, R. M
• Format: Article
• Language: English
• Subjects: Adult; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Bryostatins; Cell Count - drug effects; Chemotherapy; Down-Regulation; Drug Synergism; Female; Humans; Karyotyping; Lactones - therapeutic use; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Macrolides; Male; Medical sciences; Mice; Mice, SCID; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Subrenal Capsule Assay; Tumor Cells, Cultured - drug effects; Vincristine - therapeutic use
• ISSN: 1078-0432; 1557-3265

The down-regulation of multidrug resistance (mdr1) gene expression as detected by competitive reverse transcription-PCR and the antitumor activity of bryostatin 1 (Bryo1) are investigated in a newly established cell line from a patient with relapsed diffuse large cell lymphoma (DLCL). 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 antigen, expresses the multidrug resistance phenotype, and has t(14;18)(q32;q21) plus other chromosomal aberrations. Exposure of the WSU-DLCL2 cells to Bryo1 in culture reversed the multidrug resistance phenotype within 24 h. A functional assay revealed a 4-fold increase in [3H]vincristine accumulation in Bryo1-treated cells compared with control. Vincristine (VCR), doxorubicin, Bryo1, and 1-beta-D-arabinofuranosylcytosine showed no clinically significant activity when given alone to WSU-DLCL2-bearing severe combined immune deficiency mice. However, when given 24 h before each cytotoxic agent, Bryo1 substantially increased the antitumor activity of VCR but not 1-beta-D-arabinofuranosylcytosine. There was a statistically significant (P < 0.001) decrease in the expression of P-glycoprotein in WSU-DLCL2 tumors taken from Bryo1-treated animals compared with untreated controls. In vivo, a competitive reverse transcription-PCR assay revealed decreased mdr1 RNA expression 24 h after Bryo1 treatment. These findings taken together indicate that Bryo1-induced down-regulation of mdr1 might be one mechanism by which Bryo1 potentiates VCR activity. The sequential use of both agents resulted in clinically significant antitumor activity in this lymphoma model.