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 che motherapy and to make an optimized treatment regimen possible. The bro ad use of such factors is hindered by their relatively high costs, the ir short elimination half-lives, the occurrence of mild side effects, and the limitation of their action to the stimulation of mainly neutro phils. Therefore, exogenous preparations inducing an endogenous activa tion of hematopoiesis are being sought. In experiments in mice we have shown that carboplatin-liposomes injected intraperitoneally in a sing le 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 c an be seen as an indicator of bone marrow stimulation. Differentiation of blood cells revealed that neutrophils, lymphocytes and platelets m ultiplied. 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, leadin g to an almost total loss of antineoplastic activity against the murin e P388 leukemia. Concomitantly, cytokines are apparently induced in an d released from macrophages producing secondarily hematopoietic growth factors either directly or in combination with other cytokines. An in volvement of macrophages is indicated by the fact that an intraperiton eal pretreatment of mice with zymosan caused a partial but significant suppression of hematopoietic stimulation. In an in vitro colony formi ng assay of serum of mice treated 1, 3, or 7 days with carboplatin-lip osomes, the number of colonies increased 20-fold compared to serum fro m saline treated animals. Additionally, a combined intraperitoneal tre atment of mice with 100 mg/kg of cyclophosphamide followed by carbopla tin-liposomes one hour later demonstrated that prevention of cytostati c-induced leukopenia is possible by this method. Although the mechanis m of stimulation of hematopoiesis by carboplatin-liposomes is still pa rtially unknown our results suggest that there should be further devel opment of such a preparation for possible use in the treatment of canc er or other inherited or acquired hematopoietic disorders,