pH modulation using CsCl enhances therapeutic effects of vitamin D in LNCaP tumor bearing mice.
BACKGROUND
The downstream effects of pH modulation significantly impact the biological fate of chemotherapeutic agents and tumor responsiveness to therapy. We have studied the effects of cesium chloride (CsCl) on pH modulation and subsequent vitamin D treatment in vitamin D receptor (VDR) positive LNCaP tumors and VDR null MDA/LCC6 tumors in vivo.


METHODS
Mice bearing LNCaP or MDA/LCC6 tumors were dosed orally with CsCl (150 mg/kg) or vitamin D (1 microg/kg) alone and in combination. Tumor volume and serum PSA (LNCaP only) were measured and intracellular pH was determined, using magnetic resonance spectroscopy (MRS), at tumor and leg muscle sites. Atomic absorption spectroscopy (AAS) was used to quantitate cesium in serum, organs, and tumor tissues.


RESULTS
From day 10 onwards, statistically significant (P<0.01) differences were observed in all LNCaP treated groups as compared with control. CsCl co-administered with vitamin D, caused an apparent sensitization of efficacy in this tumor model. There were no correlating differences in serum PSA. Elevation of pH was statistically significant for all three treatment groups as compared with control. The pH measured in leg muscle was not influenced by CsCl treatment. Inhibition of tumor growth was not apparent in VDR null MDA/LCC6 tumors although intracellular tumor pH was shifted. Cesium was rapidly absorbed into serum and present in LNCaP tumors, prostates and other tissues after 1 hr, remaining for up to 24 hr.


CONCLUSIONS
The data presented in this manuscript is the first report of chemosensitization by in vivo pH modulation using CsCl in mice bearing prostate or any other tumor xenograft.
Guns
Emma S
ES
The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada.
Xie
Xiaowei
X
Fedoruk
Matthew
M
Madera
Candice
C
Cowell
Simon
S
Mayer
Lawrence D
LD
Skov
Kirsten
K
Gleave
Martin E
ME
Kozlowski
Piotr
P
D000818:Animals; D045744:Cell Line, Tumor; D002586:Cesium / Q000493:pharmacokinetics*; D002712:Chlorides / Q000493:pharmacokinetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009687:Nuclear Proteins; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013054:Spectrophotometry, Atomic; D014018:Tissue Distribution; D014807:Vitamin D / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D002712:Chlorides; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D014807:Vitamin D; D002586:Cesium; C028019:cesium chloride