Previous NMR studies demonstrated that
lonidamine (LND) selectively diminishes the intracellular pH (pHi) of DB-1
melanoma and mouse xenografts of a variety of other prevalent human
cancers while decreasing their bioenergetic status (
tumor βNTP/Pi ratio) and enhancing the activities of
melphalan and
doxorubicin in these
cancer models. Since
melphalan and
doxorubicin are highly toxic agents, we have examined three other
nitrogen (N)-mustards,
chlorambucil,
cyclophosphamide and
bendamustine, to determine if they exhibit similar potentiation by LND. As single agents LND,
melphalan and these N-mustards exhibited the following activities in DB-1
melanoma xenografts; LND: 100%
tumor surviving fraction (SF);
chlorambucil: 100% SF;
cyclophosphamide: 100% SF;
bendamustine: 79% SF;
melphalan: 41% SF. When combined with LND administered 40 min prior to administration of the N-mustard (to maximize intracellular acidification) the following responses were obtained;
chlorambucil: 62% SF;
cyclophosphamide: 42% SF;
bendamustine: 36% SF;
melphalan: 10% SF. The effect of LND on the activities of these N-mustards is generally attributed to
acid stabilization of the aziridinium active intermediate,
acid inhibition of
glutathione-S-transferase, which acts as a scavenger of aziridinium, and
acid inhibition of DNA repair by O6-alkyltransferase. Depletion of
ATP by LND may also decrease multidrug resistance and increase
tumor response. At similar maximum tolerated doses, our data indicate that
melphalan is the most effective N-mustard in combination with LND when treating DB-1
melanoma in mice, but the choice of N-mustard for coadministration with LND will also depend on the relative toxicities of these agents, and remains to be determined.