title: (31) P and (1) H MRS of DB-1 melanoma xenografts: lonidamine selectively decreases tumor intracellular pH and energy status and sensitizes tumors to melphalan.
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 (pH(i) ) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pH(e) ) 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 pH(i) 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 pH(e) and a small transient decrease in bioenergetics (32.9 ± 10.6%, p > 0.05) at 40 min post-LND. No changes in pH(i) or adenosine triphosphate/inorganic phosphate were detected in the brain (pH(i) , bioenergetics; p > 0.1) or skeletal muscle (pH(i) , pH(e) , 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; log(10) 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 pH(i) and bioenergetics may sensitize melanoma to pH-dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia.
authors: Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104-6069, USA.
authors: Kavindra
authors: K
authors: Nath
authors: David S
authors: DS
authors: Nelson
authors: Andrew M
authors: AM
authors: Ho
authors: Seung-Cheol
authors: SC
authors: Lee
authors: Moses M
authors: MM
authors: Darpolor
authors: Stephen
authors: S
authors: Pickup
authors: Rong
authors: R
authors: Zhou
authors: Daniel F
authors: DF
authors: Heitjan
authors: Dennis B
authors: DB
authors: Leeper
authors: Jerry D
authors: JD
authors: Glickson
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D006863:Hydrogen-Ion Concentration / Q000187:drug effects*; D007191:Indazoles / Q000008:administration & dosage*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008545:Melanoma / Q000737:chemistry* / Q000188:drug therapy* / Q000503:physiopathology; D008558:Melphalan / Q000008:administration & dosage*; D051379:Mice; D010761:Phosphorus Radioisotopes; D011522:Protons; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007191:Indazoles; D010761:Phosphorus Radioisotopes; D011522:Protons; D008558:Melphalan; C016371:lonidamine