Speaker Abstracts

Animal Experiments—An Essential Component for the Development of Liposomal Anticancer Agents

During several years, in our institute more than a dozen of established or novel anticancer compounds have been encapsulated in liposomes and their pharmacological behavior has been tested in in vitro and in vivo experimental models.

It was revealed, that for each substance a tailored liposomal system had to be developed. Animal experiments designed to determine both the antitumor activity and side effects of liposomal in comparison to the free drugs have shown that in the majority of cases a benefit for the vesicular formulation could be obtained. In 7/12 liposomal compounds tested (Bleomycin, Daunorubicin, Cisplatin, Carboplatin, Cyclophosphamide, CCNU, Alkylphospholipids) a substantial decrease of toxicity, mainly due to changed pharmacokinetic data could be observed. The therapeutic efficacy could be increased by use of liposomes for Bleomycin, Taxol, and Mitoxantrone while in other examples no change (Daunorubicin, Methotrexate, TNF) or even a decrease of activity (Cisplatin, Cyclophosphamide, CCNU) was registered.

Carboplatin is one example in which by liposomal encapsulation the pharmcological properties were decisively changed. While the free drug leads to leuko- and thrombopenia, the Carboplatin-liposomes (CPL) revealed after only one i.p. or i.v. injection into mice a substantial and long-standing leukocytosis. That effect was paralleled by a release of cytokines from macrophages into the serum, an increased number of peripheral blood stem cells and colony forming activity. The anticancer activity of carboplatin was remarkably improved especially in breast cancer xenografts by using the liposomal formulation. We hypothesise that CPL of specific size and constitution are efficiently taken up by macrophages/monocytes. That leads to the induction of growth factors inducing secondarily a stimulation of haematopoiesis.

Another example is the encapsulation of Tamoxifen (Tam), an antiestrogen used mainly as first line therapy in estrogen receptor positive breast cancer. Tamoxifen-containing LUVETs prepared from egg phosphocholine, dicetylphosphate and an alkylphospholipid (OPP) had a higher in vitro cytotoxicity both in Tam-sensitive and –resistant breast cancer lines. In vivo testing in xenografts with inherited or acquired Tam-resistance showed that in 2/4 models resistance could be overcome by an oral treatment with appropriate liposomes.

These both examples impressively document that only by inclusion of a consequent in vivo testing procedure the surprising pharmacological effects of liposomal anticancer agents can be revealed.