Association of carmustine with a lipid emulsion: in vitro, in vivo and preliminary studies in cancer patients

Abstract.

Purpose: We had previously shown in acute leukemia and in breast and ovary carcinoma patients that a cholesterol-rich emulsion (LDE) that binds to receptors for low-density lipoprotein (LDL) may concentrate in neoplastic tissues. In this study, the potential of LDE as a carrier for anticancer drugs was investigated. Methods: LDE was associated with carmustine, and the cytotoxicity of the LDE-carmustine complex was studied in a neoplastic cell line and its biodistribution was studied in mice. The plasma kinetics of the complex and its uptake by tumor and normal tissue were determined in cancer patients. Finally, an exploratory clinical study to determine the toxicity profile of LDE-carmustine at escalating dose levels was conducted in 42 advanced cancer patients refractory to conventional chemotherapy. Results: Carmustine formed a stable association with LDE. The pharmacological action of carmustine, as tested in cancer cells, was not diminished by association with LDE compared with the free drug and was indeed mediated by the LDL receptor. The biodistribution in mice and plasma kinetics in patients of the emulsion were not changed by association of the drug. The uptake of LDE-carmustine by tumor was severalfold greater than the uptake by the corresponding normal tissue. Finally, patients treated with LDE-carmustine showed negligible side effects even at very high dose levels. Conclusions: Association with LDE preserves the cytotoxicity of carmustine and markedly diminishes its side effects.