title: Repeated administration of inhibitors for ion pumps reduce markedly tumor growth in vivo.
abstract: BACKGROUND
  Measurements of extracellular pH show that the micro environment of malignant tumors is more acidic than that of normal cells, whereas pH does not differ appreciable in normal and malignant cells. The acid micro environment of tumors is created by the secretion of tumor factors and ATP hydrolysis in hypoxic tumor tissue. In order to survive in a low pH-environment tumor cells develop regulatory mechanisms which keep their intracellular pH stable. Two of the most important systems are the Na+/H+ ion pump and the Na-dependent HCO3-/Cl- pump of stilbenian derivatives.
  
  
  METHODS
  Experiments were carried out on DBA mice of both sexes at the age of 4 month. Laboratory animals were grown in our institute and supplied with food and aqua ad libitum.
  
  
  RESULTS
  After termination of the experiments the mean tumor diameter in the control group was 12.4 +/- 0.8mm, in group A it was 6.9 +/- 0.6mm, and in group B we measured 6.6 +/- 3.1mm. At the final day the tumor size in treated animals was twice as small as in the control group. In addition we observed the rate of survival. In the control group only 18% of the animals were still alive at day 18. Considering the rate of survival a statistically significant difference between treated and untreated animals was observed. The survival of tumor cells is dependent on the function of these ion pumps which keep their intracellular pH values constant in the setting of an acid extracellular environment.
  
  
  CONCLUSIONS
  The activity of the ion pump is especially important at the beginning of cell division and in cell proliferation. Our in vivo experiments demonstrate that prolonged administration of intratumoral ion pump inhibitors suppresses tumor growth as well as enhances survival of tumor-bearing animals. Research of inhibitors of ion pumps and their action in tumor growth opens new perspectives into pathophysiology of malignant tumors and may create new therapeutic options.
authors.forename: Igor
authors.initials: I
authors.lastname: Hrgovic
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Glavic
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Kovacic
authors.forename: Smaila
authors.initials: S
authors.lastname: Mulic
authors.forename: Lejla
authors.initials: L
authors.lastname: Zunic
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Hrgovic
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D016623:Ion Pumps / Q000037:antagonists & inhibitors*; D034801:Mastocytoma / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D047368:Tumor Burden / Q000187:drug effects*; D059016:Tumor Microenvironment
chemical_list: D016623:Ion Pumps; D000584:Amiloride; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; C039614:ethylisopropylamiloride