Antitumor effects of a novel lipophilic platinum complex (SM-11355) against a slowly-growing rat hepatic tumor after intra-hepatic arterial administration.
The antitumor effects of cis[((1R,2R)-1,2-cyclohexanediamine-N,N')bis(myristato)] platinum(II) (SM-11355) were evaluated in a rat hepatic tumor model, and were compared with those of cisplatin (CDDP). A novel slowly-growing rat hepatic tumor model was established by the successive transplantation of rat AH109A tumor into the liver. The drugs, which were suspended in Lipiodol, were administered into the proper hepatic artery of tumor-bearing rats. Tumor growth was suppressed in the group that received SM-11355 suspended in Lipiodol (SM-11355/Lipiodol). Mean tumor growth rates in the groups administered 20 microl of Lipiodol containing 0, 0.02, 0.04, 0.1, 0.2, or 0.4 mg of SM-11355 were 244, 86, 110, 81, 51, and 40%, respectively, 1 week after treatment. Those in the groups administered 20 microl of Lipiodol containing 0.1, 0.2, or 0.4 mg of CDDP were 240, 110, and 45%, respectively. In the groups administered 0.2 and 0.4 mg of SM-11355 or 0.4 mg of CDDP, massive necrosis was observed in the tumor tissue 1 week after drug administration, and the tumors disappeared 4 weeks after drug administration. Serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels were measured as markers of liver damage one day after the drug was administered into the hepatic artery of rats. The minimum toxic dose, which raised serum GOT and GPT levels significantly compared with Lipiodol alone, was 0.2 mg for SM-11355/Lipiodol and 0.1 mg for CDDP/Lipiodol, respectively. The results demonstrated that SM-11355/Lipiodol exerted antitumor activity at a dose that showed no hepatic toxicity in the rat model, but CDDP/Lipiodol did not.
Kishimoto
S
S
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
Noguchi
T
T
Yamaoka
T
T
Fukushima
S
S
Takeuchi
Y
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D007261:Infusions, Intra-Arterial; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C406530:miriplatin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase