Tong A W, Dalton W S, Tsuruo T, Fay J W, Stone M J
Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas 75246.
Prog Clin Biol Res. 1990;333:155-64.
We examined the effectiveness of a previously characterized plasma cell-reactive monoclonal antibody (MoAb), MM4, in eliminating multi-drug resistant (MDR1) multiple myeloma (MM) clonogenic colony-forming cells (CCCs). MDR1 sublines with 6-fold (RPMI8226/DOX6) and 40-fold (RPMI 8226/DOX40) resistance to doxorubicin (DOX) were selected from the chemosensitive MM parent line RPMI 8226/S. Both sublines remained reactive with plasma cell MoAbs MM4 and PCA-1, as measured by flow cytometric immunophenotype analysis. MM4 and rabbit complement (C') were cytotoxic to MDR DOX6 (74 +/- 8.5%) and DOX40 (75 +/- 11.3%) cells as well as to chemosensitive 8226/S (80 +/- 5.6%) cells. Treatment with MM4 + C' depleted up to 3 logs of chemosensitive and MDR myeloma CCCs (8226/S: 99.26 +/- 0.52%; DOX6 99.91 +/- 0.08%' DOX40 99.15 +/- 0.55%). In addition, this approach abrogated the selfrenewing capacity of chemoresistant and MDR1 myeloma cell lines, according to doubling time analyses. By comparison, the P-glycoprotein-reactive MoAb MRK-16 and C' was effective in deleting MDR1 CCCs (DOX10: 95.71 +/- 2.51%; DOX40: 99.61 +/- 0.43%) but affected chemosensitive myeloma CCCs only slightly (5.93 +/- 14.52%). When DOX40 cells were mixed with normal bone marrow (BM) in a ratio of 10:90 (MM:BM), treatment with MM4 plus C' deleted MM CCCs (98.80 +/- 0.71%) without affecting the majority of normal BM progenitors. The combination of MM4 and MRK-16 did not enhance MDR myeloma CCC depletion. These observations suggest that MM4 + C' may be useful for depleting MDR as well as chemosensitive myeloma clonogenic cells from human bone marrow.
我们检测了一种先前已鉴定的浆细胞反应性单克隆抗体（MoAb）MM4在清除多药耐药（MDR1）多发性骨髓瘤（MM）克隆形成集落细胞（CCC）方面的有效性。从化疗敏感的MM亲本系RPMI 8226/S中筛选出对阿霉素（DOX）具有6倍（RPMI8226/DOX6）和40倍（RPMI 8226/DOX40）耐药性的MDR1亚系。通过流式细胞术免疫表型分析测定，两个亚系与浆细胞MoAb MM4和PCA-1仍有反应。MM4和兔补体（C'）对MDR DOX6（74±8.5%）和DOX40（75±11.3%）细胞以及化疗敏感的8226/S（80±5.6%）细胞具有细胞毒性。用MM4 + C'处理可使化疗敏感和MDR骨髓瘤CCC减少多达3个对数（8226/S：99.26±0.52%；DOX6 99.91±0.08%；DOX40 99.15±0.55%）。此外，根据倍增时间分析，这种方法消除了化疗耐药和MDR1骨髓瘤细胞系的自我更新能力。相比之下，P-糖蛋白反应性MoAb MRK-16和C'在清除MDR1 CCC方面有效（DOX10：95.71±2.51%；DOX40：99.61±0.43%），但对化疗敏感的骨髓瘤CCC影响很小（5.93±14.52%）。当将DOX40细胞与正常骨髓（BM）以10:90（MM:BM）的比例混合时，用MM4加C'处理可清除MM CCC（98.80±0.71%），而不影响大多数正常BM祖细胞。MM4和MRK-16的组合并未增强对MDR骨髓瘤CCC的清除作用。这些观察结果表明，MM4 + C'可能有助于从人骨髓中清除MDR以及化疗敏感的骨髓瘤克隆形成细胞。
