Optimal administration schedule of cisplatin for bladder tumor with minimal induction of metallothionein.
OBJECTIVE
The metal binding protein metallothionein (MT) confers drug resistance when MT is induced in tumor tissues. Cisplatin is known to induce MT synthesis in tumor tissues, which may lead to drug resistance. We examined whether a difference in the administration schedule of cisplatin affect the efficiency of MT induction.


METHODS
Balb/c nude mice were inoculated with NMB-1 human bladder tumor tissues and injected with cisplatin (total dose of 64 micromol/kg) in a single injection or fractioned daily injections. Tumor MT concentration was determined 24 hours after the last injection of cisplatin by mercury binding assay. The effect of pretreatment with ZnCl2 on antitumor activity of cisplatin was examined in NMB-1 bearing mice.


RESULTS
Tumor MT levels increased significantly with the increase in the number of cisplatin injections. Pretreatment of NMB-1 bearing mice with ZnCl2 (200 micromol/kg x 2) caused the same level of MT induction (1.6-fold) as that of fractioned injections of cisplatin (4 x 16 micromol/kg). Pretreatment of NMB-1 bearing mice with ZnCl2 (200 micromol/kg x 2) depressed cisplatin antitumor activity by about 50%.


CONCLUSIONS
The induction of MT to a moderate extent (1.6-fold) in NMB-1 tumor inoculated in mice conferred cisplatin resistance. This level of MT induction can be achieved by fractioned daily injections of cisplatin but not by a single injection. Therefore, it is preferable to administer cisplatin as a single injection rather than as fractioned injections to achieve effective antitumor activity with minimum MT induction.
Kondo
Yukihiro
Y
Department of Urology, Nippon Medical School, Tokyo, Japan. kondoy@pharm.kitasato-u.ac.jp
Yamagata
Kenji
K
Satoh
Masahiko
M
Himeno
Seiichiro
S
Imura
Nobumasa
N
Nishimura
Taiji
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002712:Chlorides / Q000494:pharmacology; D002945:Cisplatin / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017967:Zinc Compounds / Q000494:pharmacology
D000970:Antineoplastic Agents; D002712:Chlorides; D017967:Zinc Compounds; C016837:zinc chloride; D008668:Metallothionein; D002945:Cisplatin