The effect of verapamil on a multi-drug resistant bladder carcinoma cell line and its potential as an intravesical chemotherapeutic agent.
A human bladder transitional cell carcinoma cell line, MGH-U1R, exhibits reproducible resistance to doxorubicin. We examined the effects on survival of this cell line caused by verapamil, which has been shown to reverse multi-drug resistance in vitro in other neoplastic cell lines. Both MGH-U1R and MGH-U1, the non-resistant parent cell line, were treated with varying concentrations of doxorubicin alone, verapamil alone, or both drugs simultaneously, all for one hour. Cells were then grown in drug-free medium for 10 days, stained, and counted. Standard survival curves were calculated. Verapamil alone had no significant cytotoxicity. Verapamil at concentrations of 16 micrograms./ml. and 32 micrograms./ml. decreased the IC50 of doxorubicin for MGH-U1R by a factor of 2.5. Using H3-verapamil, we also examined the systemic and local absorption of this drug resulting from intravesical verapamil administration in rabbits. All animals were treated for one hour, and multiple serum samples were drawn during treatment. Verapamil was found in high concentrations in the mucosa, less in the adventitia, and was absent in venous blood. Verapamil effectively reverses resistance to doxorubicin of MGH-U1R in vitro. The intravesical use of verapamil appears to be safe, and may prove to be a useful adjunct in the intravesical therapy of some bladder tumors.
Long
J P
JP
Urological Service, Massachusetts General Hospital, Boston 02114.
Prout
G R
GR
Wong
Y K
YK
Lin
C W
CW
D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D011817:Rabbits; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014700:Verapamil / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity
D004317:Doxorubicin; D014700:Verapamil