One strategy for improving the selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing soluble macromolecules or carrier proteins. Thus, five maleimide derivatives of chlorambucil were bound to thiolated human serum transferrin which differ in the stability of the chemical link between drug and spacer. The maleimide ester derivatives 1 and 2 were prepared by reacting 2-hydroxyethylmaleimide or 3-maleimidophenol with the carboxyl group of chlorambucil, and the carboxylic hydrazone derivatives 5-7 were obtained through reaction of 2-maleimidoacetaldehyde, 3-maleimidoacetophenone, or 3-maleimidobenzaldehyde with the carboxylic acid hydrazide derivative of chlorambucil. The alkylating activity of transferrin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)pyridine (NBP) demonstrating that on average 3 equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective transferrin conjugates in the MCF7 mammary carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugates in which chlorambucil was bound to transferrin through non-acid-sensitive linkers, i.e., an ester or benzaldehyde carboxylic hydrazone bond, were not, on the whole, as active as chlorambucil. In contrast, the two conjugates in which chlorambucil was bound to transferrin through acid-sensitive carboxylic hydrazone bonds were as active as or more active than chlorambucil in both cell lines. Especially, the conjugate in which chlorambucil was bound to transferrin through an acetaldehyde carboxylic hydrazone bond exhibited IC50 values which were approximately 3-18-fold lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil. The structure-activity relationships of the transferrin conjugates are discussed with respect to their pH-dependent acid sensitivity, their serum stability, and their cytotoxicity.

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Extracts of Viscum album (mistletoe) are widely used as complementary cancer therapies in Europe. The mistletoe lectins have been identified as the main active principle of mistletoe extracts. They have been shown to exhibit cytotoxic effects as well as immunomodulatory activities. The latter is exemplified by induction of cytokine secretion and increased activity of natural killer cells. Recent reports, however, indicated possible tumor growth stimulation by mistletoe extracts. Therefore, the three aqueous mistletoe extracts (Iscador M special, Iscador Qu special and Iscador P) were evaluated for antiproliferative and/or stimulatory effects in a panel of 16 human tumor cell lines in vitro using a cellular proliferation assay. The results show no evidence of stimulation of tumor growth by any of the three Iscador preparations, comprising central nervous system, gastric, non-small cell lung, mammary, prostate, renal and uterine cancer cell lines, as well as cell lines from hematological malignancies and melanomas. On the contrary, Iscador preparations containing a high lectin concentration (Iscador M special and Iscador Qu special) showed antitumor activity in the mammary cancer cell line MAXF 401NL at the 15 microg/ml dose level with a more than 70% growth inhibition compared to untreated control cells. In addition, a slight antitumor activity (growth inhibition 30-70%) was found in three tumor cell lines for Iscador M special and in seven tumor cell lines for Iscador Qu special, respectively. Iscador P, which contains no mistletoe lectin I, showed no antiproliferative activity.

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