Progesterone: a novel adjunct to intravesical chemotherapy.
OBJECTIVE
To investigate the effect of progesterone on multidrug-resistant urothelial cell lines, as the failure of intravesical chemotherapeutic drugs is often caused by multidrug resistance (MDR), mediated by the drug efflux pump P-glycoprotein (PGP), the function of which can be down-regulated by various compounds including steroid hormones.


METHODS
Two urothelial cell lines (RT112S and MGH-U1S) and their MDR sublines (RT112R, to cisplatin; and MGH-U1R, a cell line expressing PGP) were used to assess the cytotoxic effects of progesterone, epirubicin and their combination. Cytotoxicity was assessed using a tetrazolium-based assay and in situ confocal microscopy.


RESULTS
Cell lines sensitive to epirubicin (MGH-U1S, RT112S and RT112R) required a much lower dose of epirubicin to kill half the cells than did the MDR cell line. Progesterone was intrinsically cytotoxic to all cell lines with little difference among them. Combined therapy had no cumulative effect on epirubicin-sensitive cell lines, but reversed MDR in the MGHU1R cell line, both assessed by confocal microscopy and by the tetrazolium assay.


CONCLUSIONS
Progesterone can reverse MDR in urothelial cells in vitro. This, combined with its effects on cell differentiation and apoptosis, together with its safety and tolerability compared to other MDR agents, suggests it may be a valuable adjunct to intravesical chemotherapy.
Lewin
J
J
MDR Research Group, Department of Urology, Southampton University Hospital, Southampton, UK. mr@jlewin.fslife.co.uk
Cooper
A
A
Birch
B
B
D000283:Administration, Intravesical; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage*; D006801:Humans; D018613:Microscopy, Confocal; D011374:Progesterone / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D019459:Urothelium
D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D011374:Progesterone