Title: Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice.
Authors: Nath, Kavindra; Nelson, David S; Putt, Mary E; Leeper, Dennis B; Garman, Bradley; Nathanson, Katherine L; Glickson, Jerry D
Published In PLoS One, (2016)
Abstract: 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.
PubMed ID: 27285585
MeSH Terms: Alkylating Agents/pharmacology*; Animals; Antineoplastic Combined Chemotherapy Protocols/pharmacology*; Cell Line, Tumor; Cell Survival/drug effects; Chlorambucil/pharmacology; Cyclophosphamide/pharmacology; Doxorubicin/pharmacology; Drug Synergism; Humans; Indazoles/pharmacology*; Male; Mechlorethamine/pharmacology*; Melanoma/drug therapy; Melanoma/pathology*; Melphalan/pharmacology; Mice; Mice, Nude; Mice, SCID; Xenograft Model Antitumor Assays