Increase in thermosensitivity of tumor cells by lowering intracellular pH.
We previously reported that the thermosensitivity of tumor cells can be increased when the intracellular pH is lowered by inhibiting Na+/H+ exchange through the plasma membrane with amiloride (3,5-diamino-6-chloro-N-(diamino methylene)pyrazinecarboxamide) or its analogues and HCO3-/Cl-exchange with 4,4-diiothiocyanato-stilbene-2,2'-disulfonic acid. In this study, we investigated the effects of (3-amino-6-chloro-5- (1-homopiperidyl)-N-(diaminomethylene)pyrazine-carboxamide) (HMA), an analogue of amiloride and a potent inhibitor of Na+/H+ exchange, and R(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7- yl)oxy]acetic acid [B-3(+)], a potent inhibitor of HCO3-/Cl- exchange, on the thermosensitivity of SCK tumor cells in vitro. We observed that 10 microM of HMA could effectively increase the cell death by heating at 43 degrees in pH 6.6 medium but not in pH 7.5 medium. The B-3(+) at 50 microM alone had no effect on the thermosensitivity of cells, but it increased the thermosensitizing effect of HMA in acidic medium. Our results strongly suggested that a combination of HMA and B-3(+) may preferentially thermosensitize tumors in vivo since the interstitial environment in tumors is acidic relative to that in normal tissues.
University of Minnesota Medical School, Department of Therapeutic Radiologic Radiation Oncology, Minneapolis 55455.
C W
CW
Song
J C
JC
Lyons
R J
RJ
Griffin
C M
CM
Makepeace
E J
EJ
Cragoe
D000584:Amiloride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D027963:Chloride-Bicarbonate Antiporters; D005449:Fluorenes / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects*; D006979:Hyperthermia, Induced / Q000379:methods*; D015674:Mammary Neoplasms, Animal / Q000628:therapy*; D051379:Mice; D017923:Sodium-Hydrogen Exchangers; D013696:Temperature; D013997:Time Factors; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D027963:Chloride-Bicarbonate Antiporters; D005449:Fluorenes; D017923:Sodium-Hydrogen Exchangers; C057360:5-(N,N-hexamethylene)amiloride; D000584:Amiloride; C053396:L 644711