Drug resistance to chlorambucil in murine B-cell leukemic cells is overcome by its conjugation to a targeting peptide

Targeting drugs through small-molecule carriers with a high affinity to receptors on cancer cells can overcome the lack of target cell specificity of most anticancer drugs. These targeted carrier–drug conjugates are also capable of reversing drug resistance in cancer cells. Although many targeted dr...

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Bibliographic Details
Published in:	Anti-cancer drugs Vol. 24; no. 2; pp. 112 - 119
Main Authors:	Gellerman, Gary, Baskin, Sophia, Galia, Luboshits, Gilad, Yosef, Firer, Michael A
Format:	Journal Article
Language:	English
Published:	England Lippincott Williams & Wilkins, Inc 01-02-2013
Subjects:	Animals Antibodies Antitumor agents Cancer Cell Line, Tumor Chlorambucil Chlorambucil - chemistry Chlorambucil - pharmacology Cytotoxic agents Cytotoxicity Drug Carriers - chemistry Drug delivery Drug Delivery Systems - methods Drug development Drug resistance Drug Resistance, Neoplasm - drug effects Female Hybridoma Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Lymphocytes B Mice Mice, Inbred BALB C Myelin basic protein Peptides - chemistry Peptides - pharmacology Spleen
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Summary:	Targeting drugs through small-molecule carriers with a high affinity to receptors on cancer cells can overcome the lack of target cell specificity of most anticancer drugs. These targeted carrier–drug conjugates are also capable of reversing drug resistance in cancer cells. Although many targeted drug delivery approaches are being tested, the linkage of several and different drugs to a single carrier molecule might further enhance their therapeutic efficacy, particularly if the drugs are engineered for variable time release. This report shows that murine B-cell leukemic cells previously resistant to a chemotherapeutic drug can be made sensitive to that drug as long as it is conjugated to a targeting peptide and, in particular, when the conjugate contains multiple copies of the drug. Using a 13mer peptide (VHFFKNIVTPRTP) derived from the myelin basic protein (p-MBP), dendrimer-based peptide conjugates containing one, two, or four molecules of chlorambucil were synthesized. Although murine hybridomas expressing antibodies to either p-MBP (MBP cells) or a nonrelevant antigen (BCL-1 cells) were both resistant to free chlorambucil, exposure of the cells to the p-MBP–chlorambucil conjugate completely reversed the drug resistance in MBP, but not BCL-1 cells or normal spleen cells. Moreover, at equivalent drug doses, there was significant enhancement in the cytotoxic activity of multidrug versus single-drug copy conjugates. On the basis of these results, the use of multifunctional dendrone linkers bearing several covalently bound cytotoxic agents allows the development of more effective targeted drug systems and enhances the efficacy of currently approved drugs for B-cell leukemia.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0959-4973 1473-5741
DOI:	10.1097/CAD.0b013e32835bb17a