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

Ayad M. Al-Katib, Mitchell R. Smith, William S. Kamanda, George Pettit, Mohammed Hamdan, Anwar N. Mohamed, Bhadrani Chelladurai, Ramzi M. Mohammad

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67 Scopus citations

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 (IgGλ) 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-β-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-β-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.

Original languageEnglish (US)
Pages (from-to)1305-1314
Number of pages10
JournalClinical Cancer Research
Volume4
Issue number5
StatePublished - May 1 1998

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Al-Katib, A. M., Smith, M. R., Kamanda, W. S., Pettit, G., Hamdan, M., Mohamed, A. N., Chelladurai, B., & Mohammad, R. M. (1998). Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clinical Cancer Research, 4(5), 1305-1314.