Fig. 1. Experimental design
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1 1. Experimental design
2 VOL.38 NO. 7 Table 1. Testicular weight in each Values are the mean }SD 3: P<0.01 vs. 2 (control) Table 2. The weight of kidneys in each Values are the mean }SD a: P<0 c: P<0 d: P<0.01 vs. 2 (control)b: P<0.05 vs. 2 (control).05 vs. 2 (control), P<0.01 vs vs. 4e: P<0.05 vs. 3 (control)
3 CHEMOTHERAPY 672 間 静 注 し た12,13で は,10匹 す べ て が1週 間 以 に お い て,11で で は,8(CDDP5mg/kg 2, FOM400mg/kg 2)で 体 重 あ た り の 畢 丸 重 量 比 で, 右 ,左 と,コ る2の ン トロ ー ル で あ 右 ,左 '5に 比較 し て 統 計 学 的 に 有 意 に 低 下 し て い た (p<0.01) 8週 目 に お い て は,9は 3と しか し コ ン トロー ル で あ る 統 計学的 に有意差 は 無か った その他 の 治 療 群 で は4週,8週 と も コ ン トロー ル と比 較 して 有 意 2-a. 2 (control, HE There all are stages tubules with cells 3,準 丸 の病理 組 織所 見 成 熟 し た10週 葡 の ラ ッ トで は,精 子 細 胞 の 成 熟 度 に 違 い は あ っ て も,1つ の 精 細 管 に 精 祖 細 胞,精 鈴 に よ る影 響 は 少 な い と考 2-b. 8 (cis-platin 5 mg/kgx2 400 at mg/kg ~2 There of spermatogenesis 2-c. 8 ( ~400) There are spermatocytes no spermatids, has decreased and the number of 母細鳳 精 子 細 胞 の い ず れ も含 ん で い る(2-a) コ ン トロ ー ル 群 を み る と,10週 齢,14週 齢.18週 飴,と もに 大 are days, some 2-d. 9 (cis-platin 5 mg/kgx2 mg/kg x 2 days, Damage to 8 weeks after fosfomycin tubules with ( ~100) 400 days, 4 weeks) seminiferous hypospermatogenesis す べ て コ ン トロー ルに比べ 有 意差 は無 か った stain, ~100) seminiferous 目 左 腎 が コ ン トロ ー ル に 比 べ て 有 意 に 増 加 して い た が,他 のは き な 変 化 は 認 め ちれ ず,加 差 は な か っ た 目 に お い て, 腎 で は4,8 が コ ン トロー ル に 比 べ て 有 意 に低 下 し て い た 8週 丸 重 量(Table1) 静 注 後4週 1990 臓 重 母(Table2) 右 腎 で は4,6.8がg左 と コ ン トロー ル と 同 様 順 調 に 増 加 し た 1.睾 2.腎 体 重 あ た りの 腎 臓 の 重 量 比 を み る と4週 内 に 死 亡 し た 体 重 で あ る が 生 存 し た ラ ッ ト は4週, 8週 JULY days, fosfomycin 8 weeks) seminiferous the treatment tubules has ( ~100) recovered
4 VOL. 38 NO. 7 Table 3. Biochemical examination iif rat serum Values are the mean }SDa P<0.01 vs. : 2 (control) P<0 b. c. d:.05 vs. 2 (control)
5 CHEMOTHERAPY JULY ) LUI R C, LARECINA M C. HERBOLD D R, JOHNSON F E: Testicular cytotoxicity of intravenous doxorubicin in rats. J. Urol., 136: 940 `943, ) Lui R C, LARECINA M C, HERBOLD D R, JOHNSON F E: The protective effect of warm ischemia on doxorubicin-induced testicular toxicity in rats. Proceedings of Association for academic Surgery, P 84, ) WILKINSON P M, MAWER G E: The persistence of adriamycin in man and rats. Br. J. Clin. Pharmacol., 1: 241 `247, ) DENTINO M E, YUM M N, RHON R T, EINHORN L H, LUFT F C: The long-term effect of cis-platinum diammine dichloride (CPDD) on renal function in man. Proc. Am. Assoc. Cancer Res. 18: 116, ) LIPPMAN A L, HELSON C. HELSON L, KLANKOFF I H Clinical trials of cis-diamminedichloroplatinum (NSC ) on the allograft reaction in mice. Cancer Chemother. Rep. 57: 191 `200, 1973
6 7 ) MORIN J P, BENDIRDJIAN J P, FILLASTRE J P: Interference of fosfomycin with lysosomal membrane integrity of rat kidney cells. Drugs Exptl. (lin. Res. 4: 63-66, ) BERTELLI A, GIOVANNINI L, PAPARELLI A: Reduced gentamycin nephrotoxicity by fosfomycin association. Future Trends Chemother, 4: , ) NEUMAN M Compararive study of the renal toxicity of amikacin alone and combined with fosformycin. Int, J. Clin. Pharmacl. Res. 11: 9 ` 20, ) INOUYE S, NIIZATO T, TAKEDA U : Protective effect of fosfomycin on the experimental nephrotoxicity induced by dibekacin. J. Pharm. Dyn. 5: , ) INOUYE S, Num. T, KOMIYA I : Mode of protective action of fosfomycin against dibekacin-induced nephrotoxicity in dehydrated rats. J. Pharm. Dyn. 5: , ) PIRA M F, Zook Jr: B C, IIAIWER C: Effects of mannitol or furosemide diuresis on nephrotoxicity and physiological disposition of cisdichloro -diammineplatinum-(1i) in rats. Cancer Res. 39: , 1979 TESTICULAR CYTOTOXITY OF INTRAVENOUS CIS-PLATIN IN COMBINATION WITH FOSFOMYCIN IN RATS Department SHIN-ICHI YOSHI!, FUMIO MANABE, HIROSHI TOMOMASA, MIKINOBU OOTANI, HIROMICHI ISHIKAWA and KENKICHI KOISO of Urology, School of Medicine, Tsukuba University, Ibaraki 305, Japan In an animal model we assessed testicular cytotoxity of intravenous cis-platin (CDDP), which was combined with fosfomysin (FOM) in order to reduce renal danage. We used 10-week-old male postpubertal Fisher 334 rats, and administered CDDP (6 mg/kg, 5 mg/kg x 2 days) alone or in combination with 400 mg/kg/day of FOM. Four and eight weeks after the last injection, the weight of testes and kidneys and the serum levels of TP, BUN, CRE and NAG were measured. Four weeks after the last injection, the weight of testes in 8 (CDDP 5 mg/kg x 2 days, FOM 400 mg/kg/day) had significantly decreased and histologically a few seminiferous tubules without spermatids were found. All rats in s 12 and 13 (CDDP 5 mg/kg x 2 days) died within one week. In 9 (CDDP 5 mg/kg x 2 days) eight weeks after the last injection, the damaged testes recovered histlogically, and their weight was not significantly different that of controls. We considered that the testicular cytotoxity of cis-platin was slight and reversible, and that FOM was effective in increasing the tolerable dose of cis-platin.
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