Edwards Claire M, Lwin Seint T, Fowler Jessica A, Oyajobi Babatunde O, Zhuang Junling, Bates Andreia L, Mundy Gregory R
Vanderbilt Center for Bone Biology, Department of Cancer Biology, Vanderbilt University, 1235 Medical Research Building IV, Nashville, TN 37232-0575, USA.
Am J Hematol. 2009 May;84(5):268-72. doi: 10.1002/ajh.21374.
The proteasome inhibitor bortezomib has a striking clinical benefit in patients with multiple myeloma. It is unknown whether the bone marrow microenvironment directly contributes to the dramatic response of myeloma cells to proteasome inhibition in vivo. We have used the well-characterized 5TGM1 murine model of myeloma to investigate myeloma growth within bone and response to the proteasome inhibitor bortezomib in vivo. Myeloma cells freshly isolated from the bone marrow of myeloma-bearing mice were found to have an increase in proteasome activity and an enhanced response to in vitro proteasome inhibition, as compared with pre-inoculation myeloma cells. Treatment of myeloma-bearing mice with bortezomib resulted in a greater reduction in tumor burden when the myeloma cells were located within the bone marrow when compared with extra-osseous sites. Our results demonstrate that myeloma cells exhibit an increase in proteasome activity and an enhanced response to bortezomib treatment when located within the bone marrow microenvironment in vivo.
蛋白酶体抑制剂硼替佐米对多发性骨髓瘤患者具有显著的临床疗效。尚不清楚骨髓微环境是否直接导致骨髓瘤细胞在体内对蛋白酶体抑制产生显著反应。我们使用了特征明确的5TGM1骨髓瘤小鼠模型来研究骨髓瘤在骨内的生长情况以及在体内对蛋白酶体抑制剂硼替佐米的反应。与接种前的骨髓瘤细胞相比，从荷瘤小鼠骨髓中新鲜分离出的骨髓瘤细胞的蛋白酶体活性有所增加，并且对体外蛋白酶体抑制的反应增强。与骨外部位相比，当骨髓瘤细胞位于骨髓内时，用硼替佐米治疗荷瘤小鼠可使肿瘤负荷得到更大程度的降低。我们的结果表明，当骨髓瘤细胞位于体内骨髓微环境中时，其蛋白酶体活性会增加，并且对硼替佐米治疗的反应会增强。
