COBALAMIN ANALOGS 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 suppo rted, in a dose-dependent manner, the growth of the murine lymphoma BW 5147 and the Cbl carrier protein, human apo-transcobalamin II, reduced the required concentration of Cbl by 100-1000-fold. Any chemical modi fication of Cbl decreased its ability to support cellular viability an d proliferation, with several of the modifications abrogating activity completely, All of the Cbl analogues that promoted growth required th e presence of apo-transcobalamin II for the optimal support of cell gr owth. Generally, Cbl analogues modified at the d-position of the corri n ring and, to a lesser degree, analogues modified at the b-position s upported cell growth, whereas analogues with modifications at the e-po sition did not support cell growth. Mixing experiments demonstrated an inverse order of potency of Cbl analogues to inhibit cell growth. Thu s, Cbl analogues with modifications at the e-position were potent inhi bitors, whereas b-analogues exhibited only partial inhibitory activity at high molar excess, and d-analogues had no inhibitory activity at a ll. 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.