Fichtner I, Reszka R, Schütt M, Rudolph M, Becker M, Lemm M, Richter J, Berger I
Max-Delbrück-Center of Molecular Medicine, Berlin-Buch, Germany.
Oncol Res. 1993;5(2):65-74.
Recombinant colony stimulating factors are studied in clinical trials with the purpose being the relief of the side effects of high dose chemotherapy and to make an optimized treatment regimen possible. The broad use of such factors is hindered by their relatively high costs, their short elimination half-lives, the occurrence of mild side effects, and the limitation of their action to the stimulation of mainly neutrophils. Therefore, exogenous preparations inducing an endogenous activation of hematopoiesis are being sought. In experiments in mice we have shown that carboplatin-liposomes injected intraperitoneally in a single dose of 100 mg/kg led to a strong two-peak increase in white blood cell counts. A maximum 10-fold elevation compared to controls of free carboplatin or empty liposomes was observed on day 2 and was probably due to the release and mobilization of cells from storage compartments. The second peak of about a 6-fold increase occurred on day 7-8 and can be seen as an indicator of bone marrow stimulation. Differentiation of blood cells revealed that neutrophils, lymphocytes and platelets multiplied. We presume that this effect of carboplatin-liposomes is due to a relatively fast uptake of these vesicles by macrophages as their natural target. Within these cells carboplatin is metabolized, leading to an almost total loss of antineoplastic activity against the murine P388 leukemia. Concomitantly, cytokines are apparently induced in and released from macrophages producing secondarily hematopoietic growth factors either directly or in combination with other cytokines. An involvement of macrophages is indicated by the fact that an intraperitoneal pretreatment of mice with zymosan caused a partial but significant suppression of hematopoietic stimulation. In an in vitro colony forming assay of serum of mice treated 1, 3, or 7 days with carboplatin-liposomes, the number of colonies increased 20-fold compared to serum from saline treated animals. Additionally, a combined intraperitoneal treatment of mice with 100 mg/kg of cyclophosphamide followed by carboplatin-liposomes one hour later demonstrated that prevention of cytostatic-induced leukopenia is possible by this method. Although the mechanism of stimulation of hematopoiesis by carboplatin-liposomes is still partially unknown our results suggest that there should be further development of such a preparation for possible use in the treatment of cancer or other inherited or acquired hematopoietic disorders.
重组集落刺激因子正在临床试验中进行研究，目的是缓解高剂量化疗的副作用，并使优化治疗方案成为可能。此类因子的广泛应用受到其相对较高的成本、较短的消除半衰期、轻度副作用的出现以及其作用主要局限于刺激中性粒细胞的限制。因此，正在寻找能够诱导内源性造血激活的外源性制剂。在小鼠实验中，我们发现以100mg/kg的单剂量腹腔注射卡铂脂质体可导致白细胞计数出现强烈的双峰增加。与游离卡铂或空脂质体对照组相比，在第2天观察到最大升高10倍，这可能是由于细胞从储存隔室中释放和动员所致。约6倍增加的第二个峰值出现在第7 - 8天，可视为骨髓刺激的指标。血细胞分化显示中性粒细胞、淋巴细胞和血小板均有增殖。我们推测卡铂脂质体的这种作用是由于这些囊泡被巨噬细胞作为天然靶点相对快速摄取所致。在这些细胞内，卡铂被代谢，导致其对小鼠P388白血病的抗肿瘤活性几乎完全丧失。与此同时，细胞因子显然在巨噬细胞中被诱导并释放，这些巨噬细胞直接或与其他细胞因子联合产生继发性造血生长因子。巨噬细胞的参与表现为用酵母聚糖对小鼠进行腹腔预处理会导致造血刺激的部分但显著抑制。在对用卡铂脂质体处理1天、3天或7天的小鼠血清进行的体外集落形成试验中，与用盐水处理动物的血清相比，集落数量增加了20倍。此外，对小鼠进行100mg/kg环磷酰胺的腹腔联合治疗，1小时后再给予卡铂脂质体，结果表明通过这种方法可以预防细胞抑制剂诱导的白细胞减少。尽管卡铂脂质体刺激造血的机制仍部分未知，但我们的结果表明，这种制剂应该进一步开发，以便可能用于治疗癌症或其他遗传性或获得性造血疾病。
