Cure of multidrug-resistant human B-cell lymphoma xenografts by combinations of anti-B4-blocked ricin and chemotherapeutic drugs
Cure of multidrug-resistant human B-cell lymphoma xenografts by combinations of anti-B4-blocked ricin and chemotherapeutic drugs
复制标题
DOI：
10.1182/blood.v87.9.3892.bloodjournal8793892
复制
发表时间：
1996-05-01
期刊：
影响因子：
20.3
通讯作者：
OConnor, R
中科院分区：
文献类型：
--
作者：
Liu, CN;Lambert, JM;OConnor, R
CD-19导向的免疫毒素抗B4阻断蓖麻毒素（抗B4-bR）目前正处于治疗B细胞恶性肿瘤的临床试验中，为了探索抗B4-bR与化疗方案结合使用的潜力，我们在患有多重耐药人类播散性肿瘤的严重联合免疫缺陷（SCID）小鼠中测试了免疫毒素与两种多药化疗方案相结合的体内疗效B 细胞淋巴瘤 Namalwa/mdr-1，在体外细胞毒性研究中，免疫毒素与顺铂的组合对 Namalwa 和 Namalwa/mdr-1 细胞产生超加成杀伤作用，而抗 B4-bR 与 4-氢过氧环磷酰胺联合对两种细胞系产生加成杀伤作用。体内环磷酰胺、顺铂、长春新碱、阿霉素和依托泊苷作为单一药物，可有效延长患有Namalwa肿瘤的SCID小鼠的生存期，而只有环磷酰胺和顺铂对Namalwa/mdr-1肿瘤有效。单独使用抗 B4-bR 或单独使用药物组合 CHOE（由环磷酰胺、长春新碱、多柔比星和依托泊苷组成）治疗 Namalwa/mdr-1 小鼠，荷瘤小鼠的寿命分别延长了 58% 和 73%。然而，每天静脉推注 5 次抗 B4-bR 并随后进行 CHOE 治疗可将寿命延长 173%，并且 20% 的小鼠被治愈。与未治疗的对照组相比，单独药物组合 CCE（环磷酰胺、顺铂和依托泊苷）可将 Namalwa/mdr-1 肿瘤小鼠的寿命延长 129%。与抗 B4-bR 联合治疗CCE 对 50% 的荷瘤小鼠产生了长期治愈效果。这些结果表明，抗 B4-bR 与当前的多药治疗方案相结合可能构成治疗耐药 B 细胞恶性肿瘤的高效方法。 (C) 1996 年，美国血液学会。
The CD-19-directed immunotoxin anti-B4-blocked ricin (anti-B4-bR) is currently in clinical trials for the treatment of B-cell malignancies, To explore the potential of using anti-B4-bR with chemotherapy protocols we tested the in vivo efficacy of the immunotoxin in combination with two multi-drug chemotherapeutic regimens in severe combined immunodeficient (SCID) mice bearing disseminated tumors of the multidrug-resistant human B-cell lymphoma Namalwa/mdr-1, In cytotoxicity studies in vitro, combinations of the immunotoxin with cisplatin produced supra-additive killing effects on both Namalwa and Namalwa/mdr-1 cells, whereas anti-B4-bR combined with 4-hydroperoxy-cyclophosphamide caused additive killing of both cell lines. In vivo cyclophosphamide, cisplatin, vincristine, doxorubicin, and etoposide as single agents, were effective in prolonging the survival of SCID mice burdened with the Namalwa tumor, whereas only cyclophosphamide and cisplatin were effective on Namalwa/mdr-1 tumors. Treatment of Namalwa/mdr-1-bearing mice with anti-B4-bR alone or with the drug combination CHOE (consisting of cyclophosphamide, vincristine, doxorubicin, and etoposide) alone increased the lifespan of the tumor-burdened mice by 58% and 73%, respectively. However, treatment with five daily bolus intravenous injections of anti-B4-bR followed by CHOE increased the lifespan by 173%, and 20% of the mice were cured, The drug combination CCE (cyclophosphamide, cisplatin, and etoposide) alone could increase the lifespan of the Namalwa/mdr-1 tumor-burdened mice by 129% compared with untreated controls, Combination therapy with anti-B4-bR and CCE produced long-term cures in 50% of the tumor-burdened mice. These results suggest that anti-B4-bR in combination with current multidrug regimens may constitute a highly efficacious modality for the treatment of drug-resistant B-cell malignancies. (C) 1996 by The American Society of Hematology.