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.
Highlights
Melanoma, the most deadly of all skin cancers [1], is primarily treated by surgical excision, which is curative in about 80% of patients if the tumor is detected in its early stages
Melphalan is currently used in hyperthermic isolated limb perfusion for treatment of melanoma in transit or soft-tissue sarcomas of the limbs, and is used in the treatment of multiple myeloma, whereas doxorubicin remains in prominent use in the treatment of a wide range of malignancies
We reasoned that if we could trap the lactate produced by tumor cells inside the cytosol, we would have a method to selectively acidify cancer cells and make them susceptible to alkylating agents whose activity is enhanced by acid [13,14,15, 38] and whose lethal effect is enhanced under acidic conditions
Summary
The most deadly of all skin cancers [1], is primarily treated by surgical excision, which is curative in about 80% of patients if the tumor is detected in its early stages. The most promising approach for systemic treatment of this disease will probably be the development of multiple therapeutic approaches based on different mechanisms of action that could be administered simultaneously or sequentially in order to overcome the inherent heterogeneity of melanoma and its ability to resist almost any agent based on a single mechanism of action. Towards this end, we have been exploring the use of an existing drug, LND, to selectively sensitize melanoma and other tumors to treatment with nitrogen (N)-mustards and anthracyclines [13,14,15]. While we have previously demonstrated that LND potentiates melphalan response, we compare this N-mustard with three additional N-mustards to determine the relative efficacy of the LND-N-mustard combination for treating melanoma
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