Al-Katib A M, Smith M R, Kamanda W S, Pettit G R, Hamdan M, Mohamed A N, Chelladurai B, Mohammad R M
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Clin Cancer Res. 1998 May;4(5):1305-14.
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.
在一株新建立的复发弥漫性大细胞淋巴瘤（DLCL）患者的细胞系中，通过竞争性逆转录 - PCR检测多药耐药（mdr1）基因表达的下调情况，并研究苔藓抑素1（Bryo1）的抗肿瘤活性。该细胞系（WSU - DLCL2）在液体培养中生长，并在严重联合免疫缺陷小鼠体内形成皮下肿瘤。WSU - DLCL2是一种成熟的B细胞系（IgG lambda），EBV核抗原呈阴性，表达多药耐药表型，具有t(14;18)(q32;q21)以及其他染色体畸变。在培养中将WSU - DLCL2细胞暴露于Bryo1 24小时内可逆转多药耐药表型。功能测定显示，与对照相比，Bryo1处理的细胞中[3H]长春新碱积累增加了4倍。单独给予长春新碱（VCR）、阿霉素、Bryo1和1 - β - D - 阿拉伯呋喃糖基胞嘧啶时，对携带WSU - DLCL2的严重联合免疫缺陷小鼠无临床显著活性。然而，在每种细胞毒性药物给药前24小时给予Bryo1，Bryo1可显著增强VCR的抗肿瘤活性，但对1 - β - D - 阿拉伯呋喃糖基胞嘧啶无此作用。与未处理的对照相比，取自Bryo1处理动物的WSU - DLCL2肿瘤中P - 糖蛋白的表达有统计学意义的降低（P < 0.001）。在体内，竞争性逆转录 - PCR测定显示Bryo1处理24小时后mdr1 RNA表达降低。这些结果共同表明，Bryo1诱导的mdr1下调可能是Bryo1增强VCR活性的一种机制。在该淋巴瘤模型中，这两种药物的序贯使用产生了临床显著的抗肿瘤活性。
