Uckun F M, Chelstrom L M, Finnegan D, Tuel-Ahlgren L, Manivel C, Irvin J D, Myers D E, Gunther R
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Health Sciences Center, Minneapolis 55455.
Blood. 1992 Jun 15;79(12):3116-29.
A highly aggressive human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line (NALM-6-UM1) causes disseminated and invariably fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens. B43-PAP plus CPA was superior to either the immunotoxin or drug alone, and combined immunochemotherapy markedly improved the event-free survival (EFS) of SCID mice challenged with NALM-6-UM1 pre-B ALL cells. Notably, 90% to 100% of SCID mice challenged with 1 x 10(6) leukemia cells and then treated with B43-PAP plus CPA combined immunochemotherapy regimens became long-term survivors, a result not achieved with B43-PAP alone or CPA alone. The advantage was particularly evident in mice inoculated with 5 x 10(6) leukemia cells. While neither 15 micrograms B43-PAP (median survival, 58 days) nor 1 mg CPA (median survival, 49 days) resulted in long-term EFS of SCID mice challenged with 5 x 10(6) NALM-6-UM1 pre-B ALL cells, the probability of EFS at 6 months was 50% +/- 16% for SCID mice treated with 15 micrograms B43-PAP plus 1 mg CPA (median survival, greater than 180 days) (P less than .0001). The probability of long-term EFS was only 14% +/- 7% for mice treated with 30 micrograms B43-PAP and 0% +/- 0% for mice treated with 1 mg CPA, but 40% +/- 16% for mice treated with 30 micrograms B43-PAP plus 1 mg CPA (P less than .0001). Similarly, the probability of EFS at 6 months was 40% +/- 16% for mice treated with 2 mg CPA alone, 70% +/- 15% for mice treated with 2 mg CPA plus 15 micrograms B43-PAP, and 70% +/- 15% for mice treated with 2 mg CPA plus 30 micrograms B43-PAP. Ten SCID mice in the B43-PAP plus CPA combined immunochemotherapy arms surviving long term after the inoculation of 5 x 10(6) NALM-6-UM1 pre-B ALL cells were electively killed at 174 to 181 days to assess their leukemia burden. We found no evidence of leukemia in any of the bone marrow specimens by two-color immunofluorescence and multiparameter flow cytometry.(ABSTRACT TRUNCATED AT 400 WORDS)
一种高度侵袭性的人 CALLA+C mu+ 前体 B 急性淋巴细胞白血病（ALL）细胞系（NALM-6-UM1）可在严重联合免疫缺陷（SCID）的 CB.17 小鼠中引发播散性且必然致命的白血病。我们使用这种人前体 B ALL 的 SCID 小鼠模型，在总共 434 只 SCID 小鼠中评估并比较了 B43（抗 CD19）-商陆抗病毒蛋白（PAP）免疫毒素和环磷酰胺（CPA）作为单一试剂以及联合免疫化疗方案的抗白血病疗效。B43-PAP 加 CPA 优于单独使用免疫毒素或药物，联合免疫化疗显著提高了用 NALM-6-UM1 前体 B ALL 细胞攻击的 SCID 小鼠的无事件生存期（EFS）。值得注意的是，用 1×10⁶ 白血病细胞攻击然后接受 B43-PAP 加 CPA 联合免疫化疗方案治疗的 SCID 小鼠中，90%至 100%成为长期存活者，单独使用 B43-PAP 或单独使用 CPA 均未取得这一结果。在用 5×10⁶ 白血病细胞接种的小鼠中，这种优势尤为明显。对于用 5×10⁶ NALM-6-UM1 前体 B ALL 细胞攻击的 SCID 小鼠，15 微克 B43-PAP（中位生存期，58 天）和 1 毫克 CPA（中位生存期，49 天）均未导致长期 EFS，但用 15 微克 B43-PAP 加 1 毫克 CPA 治疗的 SCID 小鼠在 6 个月时的 EFS 概率为 50%±16%（中位生存期，大于 180 天）（P＜0.0001）。用 30 微克 B43-PAP 治疗的小鼠长期 EFS 概率仅为 14%±7%，用 1 毫克 CPA 治疗的小鼠为 0%±0%，但用 30 微克 B43-PAP 加 1 毫克 CPA 治疗的小鼠为 40%±16%（P＜0.0001）。同样，单独用 2 毫克 CPA 治疗的小鼠在 6 个月时的 EFS 概率为 40%±16%，用 2 毫克 CPA 加 15 微克 B43-PAP 治疗的小鼠为 70%±15%，用 2 毫克 CPA 加 30 微克 B43-PAP 治疗的小鼠为 70%±15%。在用 5×10⁶ NALM-6-UM1 前体 B ALL 细胞接种后，B43-PAP 加 CPA 联合免疫化疗组中有 10 只 SCID 小鼠长期存活，在 174 至 181 天时被选择性处死以评估其白血病负担。通过双色免疫荧光和多参数流式细胞术，我们在任何骨髓标本中均未发现白血病证据。（摘要截断于 400 字）
