31P and 1H MRS of DB-1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan (pages 98–105)
Kavindra Nath, David S. Nelson, Andrew M. Ho, Seung-Cheol Lee, Moses M. Darpolor, Stephen Pickup, Rong Zhou, Daniel F. Heitjan, Dennis B. Leeper and Jerry D. Glickson
Article first published online: 29 JUN 2012 | DOI: 10.1002/nbm.2824
In vivo 31P and 1H MRS demonstrates that lonidamine induces a significant decrease in intracellular pH (pHi) and bioenergetics (nucleoside triphosphate/inorganic phosphate, NTP/Pi) and an increase in steady-state lactate of melanoma xenografts. However, extracellular pH exhibits a minimal decrease. Noninvasive monitoring of brain and muscle showed no significant changes. However, liver showed a transient decrease in pHi after 20 min. The prolonged selective decrease in tumor pH and bioenergetics may be exploited for pH-dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia. Intracellular pH (A), extracellular pH (B), tumor lactate (C) and NTP/Pi (D) of human melanoma xenograft and normal tissues in mice after the administration of lonidamine (100 mg/kg intraperitoneally). (E) Growth delay experiments performed on DB-1 human melanoma xenografts in nude mice treated with 7.5 mg/kg melphalan.