Satoh M, Kloth D M, Kadhim S A, Chin J L, Naganuma A, Imura N, Cherian M G
Department of Public Health, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Cancer Res. 1993 Apr 15;53(8):1829-32.
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.
在接种小鼠膀胱肿瘤（MBT-2）的C3H小鼠中研究了金属硫蛋白（MT）在顺铂（顺式-DDP）耐药性和肾毒性中的作用。在第0天，给C3H小鼠皮下接种1×10⁶个MBT-2细胞/只。从第7天至第9天，小鼠每天皮下注射一次炔丙甘氨酸（PPG）（500 μmol/kg），共3天；从第8天至第9天，每天皮下注射一次硫酸锌（ZnSO₄）（200 μmol/kg），共2天。在接种MBT-2细胞10天后腹腔注射顺式-DDP（50 μmol/kg）。由于给予硫酸锌后肿瘤和肾脏中的MT含量显著增加，顺式-DDP的抗肿瘤活性及其肾毒性均降低。然而，联合给予PPG可降低肿瘤中MT的诱导，而不影响肾脏MT的水平。结果，PPG可以明显克服MT介导的肿瘤对顺式-DDP的耐药性，而不会损害肾脏MT对药物肾毒性的保护作用。因此，有人认为PPG可能是癌症化疗中一种有前景的辅助药物，可克服由MT水平升高引起的肿瘤耐药性。
