PMID- 16475697
OWN - NLM
STAT- MEDLINE
DCOM- 20060309
LR  - 20131121
IS  - 0250-7005 (Print)
IS  - 0250-7005 (Linking)
VI  - 26
IP  - 1A
DP  - 2006 Jan-Feb
TI  - Acridine orange used for photodynamic therapy accumulates in malignant 
      musculoskeletal tumors depending on pH gradient.
PG  - 187-93
AB  - BACKGROUND: Intra-operative photodynamic therapy has been applied with acridine 
      orange (AO-PDT) to human musculoskeletal sarcomas for the past 4 years, resulting 
      in a low local recurrence rate, within 10%, after intra-marginal tumor resection 
      and excellent limb function. However, it is still unclear why acridine orange 
      (AO) specifically accumulates in tumor cells, especially in malignant tumor 
      cells. The purpose of this study was to clarify the mechanism of AO accumulation 
      in malignant musculoskeletal tumors. MATERIALS AND METHODS: Sixty-two 
      musculoskeletal tumors, including 35 malignant and 27 benign tumors, were 
      studied. Using freshly resected tumor material, the extracellular pH (pHe) was 
      measured and the fluorescence intensity of AO accumulated in the tumors was 
      measured by an image analyzer after ex vivo exposure to 1.0 microg/ml AO, 
      followed by blue excitation. In the in vitro study, bafilomycin A1 was exposed to 
      LM 8 mouse osteosarcoma cells, in order to inhibit V-ATPase, subsequently causing 
      a decrease in the pHgradient (deltapH) between the intracellular pH (pHi) and 
      extracellular pH (pHe) or between the pHi and the pHe. AO accumulation and the 
      cytocidal effect of AO were evaluated. RESULTS: The results of the in vivo study, 
      using human materials freshly resected at surgery, revealed that the pHe of the 
      malignant musculoskeletal tumors was significantly lower than that of the benign 
      tumors and normal muscles or adipose tissues and also showed that the AO 
      fluorescence intensity of the malignant musculoskeletal tumors was significantly 
      stronger than that of the benign tumors and normal muscles or adipose tissues. 
      The results also revealed that the AO fluorescence intensity negatively 
      correlated with the pHe in tumors and normal tissues. The in vitro study showed 
      that bafilomycin A1 inhibited the accumulation of AO in acidic organelles, such 
      as lysosomes, and that the cytocidal effect of AO-PDT was also remarkably 
      inhibited. DISCUSSION: Based on results of the in vivo and in vitro studies, it 
      is suggested that malignant musculoskeletal tumors have a large deltapH between 
      the pHi and the pHe or between the pHi and the vaculolar pH and also that a large 
      ApH increases AO accumulation in tumors. We, therefore, believe that AO-PDT may 
      be more effective in highly malignant musculoskeletal tumors than low grade ones, 
      because of their acidity. CONCLUSION: AO accumulation in musculoskeletal tumors 
      was dependent on the ApH between the pHi and the pHe, or between the pHi and the 
      vacuolar pH.
FAU - Matsubara, Takao
AU  - Matsubara T
AD  - Department of Orthopedic Surgery, Mie University Faculty of Medicine, Mie, Japan.
FAU - Kusuzaki, Katsuyuki
AU  - Kusuzaki K
FAU - Matsumine, Akihiko
AU  - Matsumine A
FAU - Shintani, Ken
AU  - Shintani K
FAU - Satonaka, Haruhiko
AU  - Satonaka H
FAU - Uchida, Atsumasa
AU  - Uchida A
LA  - eng
PT  - Journal Article
PL  - Greece
TA  - Anticancer Res
JT  - Anticancer research
JID - 8102988
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Photosensitizing Agents)
RN  - F30N4O6XVV (Acridine Orange)
SB  - IM
MH  - Acridine Orange/*pharmacokinetics/pharmacology
MH  - Animals
MH  - Bone Neoplasms/drug therapy/*metabolism
MH  - Fluorescent Dyes/*pharmacokinetics/pharmacology
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Mice
MH  - Muscle Neoplasms/drug therapy/*metabolism
MH  - Osteosarcoma/drug therapy/metabolism
MH  - Photochemotherapy/*methods
MH  - Photosensitizing Agents/*pharmacokinetics/pharmacology
EDAT- 2006/02/16 09:00
MHDA- 2006/03/10 09:00
CRDT- 2006/02/16 09:00
PHST- 2006/02/16 09:00 [pubmed]
PHST- 2006/03/10 09:00 [medline]
PHST- 2006/02/16 09:00 [entrez]
PST - ppublish
SO  - Anticancer Res. 2006 Jan-Feb;26(1A):187-93.