Blumenthal R D, Sharkey R M, Forman D, Wong G, Hess J, Goldenberg D M
Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Newark, NJ 07103, USA.
Exp Hematol. 1995 Sep;23(10):1088-97.
Myelosuppressive toxicity is dose-limiting for radioimmunotherapy. We have reported on the use of cytokine intervention (rhIL-1 and rmGM-CSF) to stimulate differentiation of progenitor cells and reduce radioantibody-induced leukopenia and thrombocytopenia (J. Natl. Cancer Inst. 84:399, 1992; Cancer 73:1073, 1994). As an alternative to the use of cytokines, we investigated the effect of syngeneic bone marrow transplantation on the ability to dose-escalate radioantibody. Injection of 10(7) bone marrow cells from a donor mouse 6 to 8 days after a 340- to 360-microCi dose of radioantibody (LD100/28)--a 25 to 30% increase above the maximal tolerated dose--resulted in 100% survival. This observation is associated with a recovery in neutrophil and thrombocyte counts within 21 days of therapy (normal recovery after 275 microCi takes 42 days). None of the mice survived when BMT was done at either 4 or 11 days after radioantibody. Marrow from normal donor mice was more effective than that from cytokine-primed mice whose marrow cells were actively cycling after a 5-day course of IL-1/GM-CSF. The combination of the two myeloprotective approaches, BMT plus a 14-day schedule of IL-1 (2 x 10(3) U/d) and GM-CSF (1 microgram/d) intervention, provided a greater stimulation of peripheral WBC counts than either approach alone; however, further dose escalation under these conditions was not feasible. The 30% intensification in radioantibody dose offers a therapeutic advantage for both bulky disease (GW-39 subcutaneous nude mouse model) and micrometastatic disease (GW-39 intrapulmonary model). In the bulky tumor model, the increase in administered dose resulting from BMT extends the 8-week growth delay observed at 275 microCi 131I-MN-14 IgG by an additional 7 weeks. In the metastatic model, dose intensification increased median animal survival from 15 to 23 weeks. Therefore, by optimizing the use of BMT, a greater therapeutic benefit can be derived from radioantibody therapy in a solid tumor model. This study represents a proof of principle, that BMT can be effective for low-dose-rate therapy as it has been for short-duration intense chemotherapy and radiation therapy. It also highlights several important issues to consider when attempting to apply the method in the clinic.
骨髓抑制毒性是放射免疫治疗的剂量限制性因素。我们曾报道过使用细胞因子干预（重组人白细胞介素-1和重组小鼠粒细胞-巨噬细胞集落刺激因子）来刺激祖细胞分化，并减少放射性抗体诱导的白细胞减少和血小板减少（《国家癌症研究所杂志》84:399，1992；《癌症》73:1073，1994）。作为使用细胞因子的替代方法，我们研究了同基因骨髓移植对增加放射性抗体剂量能力的影响。在给予340至360微居里剂量的放射性抗体（LD100/28）后6至8天，注射来自供体小鼠的10⁷个骨髓细胞——比最大耐受剂量增加25%至30%——导致100%存活。这一观察结果与治疗后21天内中性粒细胞和血小板计数的恢复有关（275微居里剂量后正常恢复需要42天）。在放射性抗体给药后4天或11天进行骨髓移植时，没有小鼠存活。正常供体小鼠的骨髓比经细胞因子预处理的小鼠的骨髓更有效，后者的骨髓细胞在接受5天的白细胞介素-1/粒细胞-巨噬细胞集落刺激因子治疗后处于活跃增殖状态。两种骨髓保护方法的联合，即骨髓移植加上14天的白细胞介素-1（2×10³单位/天）和粒细胞-巨噬细胞集落刺激因子（1微克/天）干预方案，对外周白细胞计数的刺激作用比单独使用任何一种方法都更大；然而，在这些条件下进一步增加剂量是不可行的。放射性抗体剂量增加30%对大块疾病（GW - 39皮下裸鼠模型）和微转移疾病（GW - 39肺内模型）都具有治疗优势。在大块肿瘤模型中，骨髓移植导致给药剂量增加使在275微居里¹³¹I - MN - 14 IgG时观察到的8周生长延迟又延长了7周。在转移模型中，剂量增加使动物中位生存期从15周延长至23周。因此，通过优化骨髓移植的使用，在实体瘤模型中放射抗体治疗可获得更大的治疗益处。这项研究证明了一个原理，即骨髓移植对低剂量率治疗可能有效，就像它对短期强化化疗和放射治疗有效一样。它还突出了在临床应用该方法时需要考虑的几个重要问题。
