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

Abstract
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.
AuthorsA M Al-Katib, M R Smith, W S Kamanda, G R Pettit, M Hamdan, A N Mohamed, B Chelladurai, R M Mohammad
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 4 Issue 5 Pg. 1305-14 (May 1998) ISSN: 1078-0432 [Print] United States
PMID9607591 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Bryostatins
  • Lactones
  • Macrolides
  • Neoplasm Proteins
  • bryostatin 1
  • Vincristine
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
  • Adult
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Bryostatins
  • Cell Count (drug effects)
  • Down-Regulation
  • Drug Synergism
  • Female
  • Humans
  • Karyotyping
  • Lactones (therapeutic use)
  • Lymphoma, Large B-Cell, Diffuse (drug therapy, genetics, pathology)
  • Macrolides
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Proteins (metabolism)
  • Subrenal Capsule Assay
  • Tumor Cells, Cultured (drug effects)
  • Vincristine (therapeutic use)

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