Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study
Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study
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DOI：
10.1007/s002800051121
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发表时间：
1999-12-01
影响因子：
3
通讯作者：
Levine, BS
中科院分区：
文献类型：
--
作者：
Brown, AP;Morrissey, RL;Levine, BS
目的：癌症化学预防是使用药物或天然药物来抑制癌症的发展。二氟甲基鸟氨酸（DFMO）是鸟氨酸脱羧酶的不可逆抑制剂，鸟氨酸脱羧酶是多胺生物合成的限速酶。DFMO已在肿瘤发生的动物模型中证明了化学预防功效。他莫昔芬（TAM）目前用于治疗雌激素受体阳性乳腺癌，并已证明其在乳腺癌高危女性的化学预防中有效。国家癌症研究所正在考虑将他莫昔芬与DFMO联合给药作为一种潜在的乳腺癌化学预防药物方案。方法：雌性大鼠连续灌胃给予DFMO和TAM 13周后，评价其毒性。剂量组为溶媒对照、DFMO（1000 mg/kg/天）、低TAM（0.25 mg/kg/天）、高TAM（2.5 mg/kg/天）、低组合（1000 ± 0.25）和高组合（1000 ± 2.5）。结果：研究中未发生死亡。毒性的临床体征仅限于由DFMO产生的结痂和擦伤组成的皮肤病变。DFMO或TAM的给药导致体重增加减少，同时给药具有累加效应。所有药物给药剂量组的血清白蛋白、总蛋白、胆固醇和甘油三酯水平均降低，但未观察到肝脏病变的组织学证据。TAM导致红细胞数量增加，而DFMO产生轻微贫血反应。DFMO在小肠中产生病变，包括隐窝上皮坏死和隐窝微脓肿，TAM联合给药可增强病变。给予TAM导致卵巢、输卵管、阴道、宫颈和子宫的组织学变化，表明在动情前期出现了排卵抑制和生殖周期停滞。与DFMO联合给药不影响TAM引起的生殖系统变化。结论：DFMO与他莫昔芬的联合给药不会导致联合药物方案特有的毒性，而是由每种药物的给药引起的毒性。在研究条件下，DFMO与他莫昔芬双重给药产生的总体毒性相对于单独使用每种药物的毒性是相加的。
Purpose: Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM) is currently used for treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of tamoxifen with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma. Methods: The toxicity of DFMO in combination with TAM was evaluated in female rats following 13 weeks of daily administration by gavage. Dose groups were vehicle control, DFMO (1000 mg/kg per day), low TAM (0.25 mg/kg per day), high TAM (2.5 mg/kg per day), low combination (1000 + 0.25) and high combination (1000 + 2.5). Results: No mortalities occurred in the study. Clinical signs of toxicity were limited to dermal lesions consisting of scab formation and abrasions produced by DFMO. Administration of either DFMO or TAM resulted in decreased body weight gains, with coadministration having an additive effect. Serum albumin, total protein, cholesterol and triglyceride levels were decreased in all drug-treated dose groups, although histologic evidence of liver lesions were not seen. TAM resulted in increased numbers of red blood cells, whereas DFMO produced a slightly anemic response. DFMO produced lesions in the small intestine consisting of necrosis of crypt epithelium and crypt microabscess, which were enhanced by TAM coadministration. Administration of TAM resulted in histologic changes in the ovaries, fallopian tube, vagina, cervix and uterus, indicating that inhibition of ovulation and reproductive cycle arrest in the proestrus stage had occurred. Coadministration with DFMO did not affect the changes to the reproductive system induced by TAM. Conclusions: Coadministration of DFMO with tamoxifen did not result in toxicity unique to the combination drug regimen, but rather toxicity resulted from administration of each drug. Under the conditions of the study, the overall toxicity produced by dual administration of DFMO with tamoxifen was additive with respect to the toxicity associated with each agent alone.