ABSTRACT
To improve the biological profile of 20(S)-camptothecin, a novel class of 20-O-linked camptothecin glycoconjugates has been designed for preferential cellular uptake into tumor cells by an active transport mechanism. Such conjugates have been optimized for enhanced solubility, stabilization of the camptothecin lactone ring, sufficient hydrolytic and proteolytic stability, and for an overall improvement in tumor selectivity. The constitution of the peptide spacer has a major impact on stability and biological activity of the conjugates both in vitro and in vivo. Glycoconjugates 17-22 with valine residues at the linkage position to camptothecin are sufficiently stable and show good antitumor activity in vitro against HT29 and other tumor cell lines. Fluorescence microscopy and flow cytometry experiments indicate that glycoconjugates such as 19 are taken up into lysosomal compartments of the tumor cell line HT29 by an active transport mechanism. The steric configuration of the particular amino acid residues linked to the camptothecin moiety has a major impact on the in vivo activity of the corresponding glycoconjugates in the breast cancer xenograft MX-1 model. Inhibiting tumor growth by >96%, the glycoconjugates 19 and 21 show the best activity in this particular model and have been investigated more extensively. The glycoconjugate 19 compares favorably to topotecan 4 and glycoconjugate 21 with respect to toxicity against hematopoietic stem cells and hepatocytes. Based on its profile, 19 has been selected for clinical trials.
Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Camptothecin/chemical synthesis , Dipeptides/chemical synthesis , Glycoconjugates/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Camptothecin/chemistry , Camptothecin/pharmacology , Cells, Cultured , Dipeptides/chemistry , Dipeptides/pharmacology , Dogs , Drug Design , Drug Screening Assays, Antitumor , Female , Flow Cytometry , Glycoconjugates/chemistry , Glycoconjugates/pharmacology , Hematopoiesis/drug effects , Hepatocytes/drug effects , Hepatocytes/enzymology , Humans , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Microscopy, Fluorescence , Rats , Solubility , Structure-Activity Relationship , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
The discovery of the natural product 20(S)-Camptothecin as a highly promising anticancer lead compound in the early 1960s; the identification of topoisomerase I as the molecular target of camptothecin compounds almost 20 years later; the approval and clinical success of irinotecan and topotecan as the first representatives of this novel class of chemotherapeutics another decade later; and the recent efforts to improve drug potency, stability, bioavailability and tumor selectivity: this is the story of camptothecin antitumor agents which will be reviewed.
ABSTRACT
Two tyrosine-O-sulfate containing cholecystokinin-related peptides were synthetized, i.e. the undeca- and the dodecapeptide amide corresponding to the C-terminus of this gut hormone; in the undecapeptide the N-terminal serine was O-substituted with the 2-deoxy-alpha-D-galactosyl group. Within the limits of error of the biological assay systems the two CCK peptides exhibited potencies in stimulating amylase secretion from dispersed rat pancreatic acini comparable to those of the CCK deca-, nona- and octapeptide.
