Cobalamin analogues modulate the growth of leukemia cells in vitro

Analogues of cyanocobalamin (CN-Cbl), with functional groups attached to either the various propionamide groups of the corrin ring or to the ribose-nucleotide linker arm, have been evaluated in a cobalamin (Cbl)-dependent in vitro cell growth assay. In this bioassay, CN-Cbl supported, in a dose-depe...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1997-09, Vol.57 (18), p.4015-4022
Main Authors: MCLEAN, G. R, PATHARE, P. M, WILBUR, D. S, MORGAN, A. C, WOODHOUSE, C. S, SCHRADER, J. W, ZILTENER, H. J
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Cell Division - drug effects
General aspects
Growth Inhibitors - pharmacology
Humans
Leukemia, Experimental - drug therapy
Leukemia, Experimental - pathology
Medical sciences
Mice
Pharmacology. Drug treatments
Structure-Activity Relationship
Transcobalamins - metabolism
Tumor Cells, Cultured - drug effects
Vitamin B 12 - analogs & derivatives
Vitamin B 12 - pharmacology
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Summary:Analogues of cyanocobalamin (CN-Cbl), with functional groups attached to either the various propionamide groups of the corrin ring or to the ribose-nucleotide linker arm, have been evaluated in a cobalamin (Cbl)-dependent in vitro cell growth assay. In this bioassay, CN-Cbl supported, in a dose-dependent manner, the growth of the murine lymphoma BW5147 and the Cbl carrier protein, human apo-transcobalamin II, reduced the required concentration of Cbl by 100-1000-fold. Any chemical modification of Cbl decreased its ability to support cellular viability and proliferation, with several of the modifications abrogating activity completely. All of the Cbl analogues that promoted growth required the presence of apo-transcobalamin II for the optimal support of cell growth. Generally, Cbl analogues modified at the d-position of the corrin ring and, to a lesser degree, analogues modified at the b- position supported cell growth, whereas analogues with modifications at the e-position did not support cell growth. Mixing experiments demonstrated an inverse order of potency of Cbl analogues to inhibit cell growth. Thus, Cbl analogues with modifications at the e-position were potent inhibitors, whereas b-analogues exhibited only partial inhibitory activity at high molar excess, and d-analogues had no inhibitory activity at all. These results indicate that modifications at the e-position of Cbl abolish the ability of Cbl to support cell growth and generate potent inhibitors of Cbl-dependent cell growth.
ISSN:0008-5472
1538-7445