Protodynamic therapy for bladder cancer: in vitro results of a novel treatment concept.
OBJECTIVE
To present a novel treatment approach for urinary bladder cancer, protodynamic therapy, which comprises inhibition of cancer cell proliferation by intracellular acidification; cis-urocanic acid (cis-UCA) was investigated as a protodynamic drug in bladder cancer cell cultures and compared with conventional chemotherapeutic agents.


METHODS
The moderately differentiated cell line 5637 and the poorly differentiated T24 cell line were exposed to cis-UCA for 0.25-2 h, and to epirubicin, doxorubicin, cisplatin and paclitaxel for 2 h, to simulate drug exposure on intravesical instillation. The combination of cis-UCA and chemotherapeutic agents was also studied. Cell viability was measured with a colorimetric assay.


RESULTS
cis-UCA inhibited proliferation and suppressed the survival of cells at an extracellular pH <or= pK(a2) of 6.65 but to a lesser degree at pH > pK(a2), as suggested by the protodynamic theory. cis-UCA caused dose-dependent, irreversible termination of cell proliferation. The number of viable surviving BC cells decreased by >85% with 2%cis-UCA (P < 0.001). Viable cells disappeared completely with 4% and 6%cis-UCA after a 2-h treatment, and by 90% with 6%cis-UCA within a 15-min exposure. These effects were associated with distinct morphological changes. The other drugs tested had a clearly lower effect on cell survival. Interestingly, when combined, cis-UCA markedly enhanced the cytotoxic effect of epirubicin.


CONCLUSIONS
cis-UCA is a potent antiproliferative agent in bladder cancer cell cultures. As our previous non-clinical studies showed that cis-UCA is locally and systemically well tolerated, protodynamic therapy with cis-UCA is a promising intravesical treatment for bladder cancer.
Laihia
Jarmo K
JK
BioCis Pharma Ltd, Turku, Finland. jarmo.laihia@biocis.com
Pylkkänen
Liisa
L
Laato
Matti
M
Boström
Peter J
PJ
Leino
Lasse
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017239:Paclitaxel / Q000008:administration & dosage; D010778:Photochemotherapy / Q000379:methods*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014560:Urocanic Acid / Q000008:administration & dosage
D015251:Epirubicin; D004317:Doxorubicin; D014560:Urocanic Acid; D017239:Paclitaxel; D002945:Cisplatin