Ruble G, Wu C, Squire R A, Ganswo O A, Strand M
Division of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA.
Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):609-16. doi: 10.1016/0360-3016(95)02119-1.
The goals of this study were to learn whether the DOTA chelator was useful for targeting lead radionuclides (203,212 Pb) to cells and tissues invaded by the Rauscher leukemia virus (RVB3) and to investigate the therapeutic efficacy of targeted 212Pb in treating the murine leukemia.
Five to 6-week-old BALB/c mice were inoculated i.v. with RVB3. This virus causes marked splenomegaly and death by day 13 and day 70 postinfection, respectively. Biodistribution, tumor targeting, and toxicity studies were performed using varying doses of 212Pb-DOTA-103A. A heavy metal chelator, DMPS, was administered orally and parenterally in two phases of the toxicity study.
Biodistribution studies showed marked tumor targeting (58% ID/g spleen) in mice treated with 203Pb-103A as compared with mice treated with control antibody B3 (4.6% ID/g spleen). Histologic cure was achieved in all leukemic mice treated with 20 muCi212Pb-103A; however, all of the mice died with leukopenia and secondary++ bacterial infections due to severe bone marrow toxicity. Nonleukemic mice and mice treated with 20 muCi212Pb-B3 experienced less marrow toxicity and longer survival. Coadministration of the heavy metal chelator did not diminish the bone marrow toxicity.
An effective, nonlethal dose could not be established to treat this tumor. The severe bone marrow toxicity associated with this radionuclide may limit its usefulness in systemic radioimmunotherapy.
本研究的目的是了解DOTA螯合剂是否有助于将铅放射性核素（203、212Pb）靶向到被劳舍尔白血病病毒（RVB3）侵袭的细胞和组织，并研究靶向212Pb治疗小鼠白血病的疗效。
将5至6周龄的BALB/c小鼠经静脉接种RVB3。该病毒分别在感染后第13天和第70天导致明显的脾肿大和死亡。使用不同剂量的212Pb-DOTA-103A进行生物分布、肿瘤靶向和毒性研究。在毒性研究的两个阶段，口服和胃肠外给予重金属螯合剂二巯基丙磺酸钠（DMPS）。
生物分布研究显示，与用对照抗体B3治疗的小鼠（4.6% ID/g脾脏）相比，用203Pb-103A治疗的小鼠具有明显的肿瘤靶向性（58% ID/g脾脏）。所有接受20 μCi 212Pb-103A治疗的白血病小鼠均实现了组织学治愈；然而，由于严重的骨髓毒性，所有小鼠均死于白细胞减少症和继发性++细菌感染。非白血病小鼠和接受20 μCi 212Pb-B3治疗的小鼠骨髓毒性较小，生存期较长。同时给予重金属螯合剂并没有减轻骨髓毒性。
无法确定治疗该肿瘤的有效、非致死剂量。与这种放射性核素相关的严重骨髓毒性可能会限制其在全身放射免疫治疗中的应用。
