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.
|
Authors | A M Al-Katib, M R Smith, W S Kamanda, G R Pettit, M Hamdan, A N Mohamed, B Chelladurai, R M Mohammad |
Journal | Clinical 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 |
PMID | 9607591
(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)
|