Seligman P A, Moran P L, Schleicher R B, Crawford E D
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Am J Hematol. 1992 Dec;41(4):232-40. doi: 10.1002/ajh.2830410403.
Gallium, when bound to transferrin, has been previously shown to cause tumor cell cytotoxicity by preventing cellular uptake of transferrin bound iron in vitro. Patients treated with constant infusion gallium nitrate for carcinoma show a rise in serum iron within 6 hr of the start of treatment. Serum iron returns to baseline by 24 hr post-infusion. Atomic analysis of iron and gallium content of Sephadex G-150 fractions of treatment sera indicate that about an equimolar amount of gallium and iron are associated with transferrin. These gallium and iron concentrations result in inhibition of transferrin mediated iron uptake in vitro, and in vivo allow for > 90% saturation of transferrin with metal. All seven patients who completed two courses of gallium therapy exhibited hypochromic microcytic anemia (mean fall in hemoglobin 3.5 grams %). Evidence for red cell iron depletion was confirmed by an increase (mean 3.3-fold) in zinc protoporphyrin levels. Since transferrin receptor increases on gallium treated iron requiring cells in vitro, we assessed cell surface transferrin receptor on peripheral blood lymphocytes by measuring fluorescent transferrin receptor antibody binding. A population of highly transferrin receptor positive cells peaks at 48 hr into the infusion. DNA analysis as well as double staining indicate the majority of transferrin receptor positive cells are unstimulated B lymphocytes. These studies provide the first documentation that constant infusion gallium treatment results in significant interference with iron metabolism and evidence for tissue iron depletion in vivo. These changes may correlate with therapeutic effects of gallium such as tumor response.
镓与转铁蛋白结合后，先前已证实在体外可通过阻止细胞摄取与转铁蛋白结合的铁来引起肿瘤细胞的细胞毒性。用硝酸镓持续输注治疗癌症的患者在治疗开始后6小时内血清铁升高。输注后24小时血清铁恢复至基线水平。对治疗血清的Sephadex G - 150组分中的铁和镓含量进行原子分析表明，约等摩尔量的镓和铁与转铁蛋白结合。这些镓和铁的浓度在体外可抑制转铁蛋白介导的铁摄取，在体内可使转铁蛋白的金属饱和度> 90%。完成两个疗程镓治疗的所有7例患者均出现低色素小细胞性贫血（血红蛋白平均下降3.5克%）。红细胞铁耗竭的证据通过锌原卟啉水平升高（平均升高3.3倍）得到证实。由于在体外镓处理的需铁细胞上转铁蛋白受体增加，我们通过测量荧光转铁蛋白受体抗体结合来评估外周血淋巴细胞上的细胞表面转铁蛋白受体。一群高度转铁蛋白受体阳性细胞在输注48小时达到峰值。DNA分析以及双重染色表明，大多数转铁蛋白受体阳性细胞是未受刺激的B淋巴细胞。这些研究首次证明持续输注镓治疗会严重干扰铁代谢，并提供了体内组织铁耗竭的证据。这些变化可能与镓的治疗效果如肿瘤反应相关。
