Carboplatin-liposomes as activators of hematopoiesis

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.