Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis.
The role of metallothionein (MT) in cisplatin (cis-DDP) resistance and renal toxicity was investigated in C3H mice inoculated with mouse bladder tumor (MBT-2). C3H mice were inoculated s.c. with 1 x 10(6) MBT-2 cells/mouse on day 0. Mice were given injections of proparglyglycine (PPG) (500 mumol/kg s.c.) once a day for 3 days from day 7 to day 9 and with ZnSO4 (200 mumol/kg s.c.) once a day for 2 days from day 8 to day 9. cis-DDP (50 mumol/kg i.p.) was administered 10 days after MBT-2 cell inoculation. Since MT contents in the tumor and kidneys were significantly increased by administration of ZnSO4, both the antitumor activity of cis-DDP and its renal toxicity were reduced. However, coadministration of PPG reduced MT induction in tumor without affecting the level of renal MT. As a result, PPG could clearly overcome the MT-mediated cis-DDP resistance of tumors without compromising the protective effect exerted by renal MT on nephrotoxicity of the drug. It was suggested, therefore, that PPG may be a promising adjunct in cancer chemotherapy to overcome the drug resistance of tumors caused by the elevated level of MT.
Satoh
M
M
Department of Public Health, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Kloth
D M
DM
Kadhim
S A
SA
Chin
J L
JL
Naganuma
A
A
Imura
N
N
Cherian
M G
MG
D000480:Alkynes; D000818:Animals; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors*; D004351:Drug Resistance; D005260:Female; D005978:Glutathione / Q000032:analysis; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013431:Sulfates / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology; D019287:Zinc Sulfate
D000480:Alkynes; D013431:Sulfates; C009055:propargylglycine; D019287:Zinc Sulfate; D008668:Metallothionein; D010293:Pargyline; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D015032:Zinc; D002945:Cisplatin; D005998:Glycine