PMID- 9525814
OWN - NLM
STAT- MEDLINE
DCOM- 19980520
LR  - 20190909
IS  - 0167-594X (Print)
IS  - 0167-594X (Linking)
VI  - 36
IP  - 2
DP  - 1998 Jan
TI  - Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition 
      of lactate efflux and intracellular acidification.
PG  - 149-57
AB  - Malignant gliomas have been associated with a high rate of glycolytic activity 
      which is believed necessary to sustain cellular function and integrity. Since 
      lonidamine (LND) is believed to reduce tumor glucose utilization by inhibition of 
      the mitochondrially-bound glycolytic enzyme hexokinase (HK), 31P magnetic 
      resonance spectroscopy (MRS) was used to noninvasively follow the effects of LND 
      on both tumor pH and the high-energy phosphate metabolites: ATP, phosphocreatine 
      (PCr) and inorganic phosphate (Pi) in subcutaneous rat 9L gliosarcomas. 31P tumor 
      spectra acquired in 5 min intervals pre- and post LND administration of 50 and 
      100 mg/kg, i.p. revealed an acidotic pH shift of -0.25 and -0.45 pH units, 
      respectively within 30 min post administration. The ATP/Pi ratio of 9L tumors 
      decreased to 40% of control and Pi levels increased to 280% of control over a 3 
      hr period. LND exerted no effect on tumor blood flow and mean arterial blood 
      pressure. Brain and muscle metabolite levels and pH were also unaffected by LND. 
      In vitro measurements of cultured 9L tumor cell intra- and extracellular lactate, 
      pentose phosphate pathway (PPP) and hexokinase (HK) activities suggest that the 
      mode of action of LND involves inhibition of lactate efflux and intracellular 
      acidification. The selective reduction of tumor energy metabolites and pH by LND 
      may be exploitable for sensitizing gliomas to radiation, chemotherapy or 
      hyperthermia.
FAU - Ben-Yoseph, O
AU  - Ben-Yoseph O
AD  - Department of Radiology, University of Michigan, Ann Arbor 48109-0648, USA.
FAU - Lyons, J C
AU  - Lyons JC
FAU - Song, C W
AU  - Song CW
FAU - Ross, B D
AU  - Ross BD
LA  - eng
GR  - R01 CA44114/CA/NCI NIH HHS/United States
GR  - R29 CA59009/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurooncol
JT  - Journal of neuro-oncology
JID - 8309335
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indazoles)
RN  - 0 (Phosphorus Radioisotopes)
RN  - 33X04XA5AT (Lactic Acid)
RN  - U78804BIDR (lonidamine)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Brain Neoplasms/drug therapy/enzymology/*metabolism
MH  - Gliosarcoma/drug therapy/enzymology/*metabolism
MH  - Hydrogen-Ion Concentration
MH  - Indazoles/*pharmacology
MH  - Injections, Subcutaneous
MH  - Intracellular Fluid/*metabolism
MH  - Lactic Acid/*metabolism
MH  - Magnetic Resonance Spectroscopy
MH  - Male
MH  - Muscle Neoplasms
MH  - Neoplasm Transplantation
MH  - Phosphorus Radioisotopes
MH  - Rats
MH  - Rats, Inbred F344
MH  - Thigh
EDAT- 1998/04/03 00:00
MHDA- 1998/04/03 00:01
CRDT- 1998/04/03 00:00
PHST- 1998/04/03 00:00 [pubmed]
PHST- 1998/04/03 00:01 [medline]
PHST- 1998/04/03 00:00 [entrez]
AID - 10.1023/a:1005819604858 [doi]
PST - ppublish
SO  - J Neurooncol. 1998 Jan;36(2):149-57. doi: 10.1023/a:1005819604858.