31P and 1H MRS of DB‐1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan. (29th June 2012)

• Record Type: Journal Article
• Authors: Nath, Kavindra; Nelson, David S.; Ho, Andrew M.; Lee, Seung‐Cheol; Darpolor, Moses M.; Pickup, Stephen; Zhou, Rong; Heitjan, Daniel F.; Leeper, Dennis B.; Glickson, Jerry D.
• Is Part Of: NMR in biomedicine. Volume 26:Number 1(2013:Jan.)
• Page Start: 98
• Page End: 105
• Publication Date: 2012-06-29
• Subjects: 31P MRS -- lonidamine -- monocarboxylic acid transporter -- tumor acidification -- melphalan -- melanoma; Nuclear magnetic resonance -- Periodicals; Magnetic Resonance Spectroscopy -- Periodicals; 574
• DOI: 10.1002/nbm.2824
• Languages: English
• ISSNs: 0952-3480

Abstract

Abstract : In vivo 31 P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg intraperitoneally) exhibit a decrease in intracellular pH (pHi ) from 6.90 ± 0.05 to 6.33 ± 0.10 ( p < 0.001), a slight decrease in extracellular pH (pHe ) from 7.00 ± 0.04 to 6.80 ± 0.07 ( p > 0.05) and a monotonic decline in bioenergetics (nucleoside triphosphate/inorganic phosphate) of 66.8 ± 5.7% ( p < 0.001) relative to the baseline level. Both bioenergetics and pHi decreases were sustained for at least 3 h following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units ( p > 0.05) at 20 min post‐LND, with no significant change in pHe and a small transient decrease in bioenergetics (32.9 ± 10.6%, p > 0.05) at 40 min post‐LND. No changes in pHi or adenosine triphosphate/inorganic phosphate were detected in the brain (pHi, bioenergetics; p > 0.1) or skeletal muscle (pHi, pHe, bioenergetics; p > 0.1) for at least 120 min post‐LND. Steady‐state tumor lactate monitored by 1 H MRS with a selective multiquantum pulse sequence with Hadamard localization increased approximately three‐fold ( p = 0.009). Treatment with LND increased the systemic melanoma response to melphalan (LPAM; 7.5 mg/kg intravenously), producing a growth delay of 19.9 ± 2.0 days (tumor doubling time, 6.15 ± 0.31 days; log10 cell kill, 0.975 ± 0.110; cell kill, 89.4 ± 2.2%) compared with LND alone of 1.1 ± 0.1 days and LPAM alone of 4.0 ± 0.0 days. The study demonstrates that the effects of LND on tumor pHi and bioenergetics may sensitize melanoma to pH‐dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia. Copyright © 2012 John Wiley & Sons, Ltd. Abstract : In vivo 31 P and 1 H 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.