首页> 外文期刊>Investigational new drugs. >Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl- p -L-fluorophenylalanine ethyl ester (J1) in vivo.
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Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl- p -L-fluorophenylalanine ethyl ester (J1) in vivo.

机译:新型二肽甲磺酰-对-L-氟苯丙氨酸乙酯(J1)的体内抗肿瘤功效和急性毒性。

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The novel alkylating dipeptide melphalanyl- p -L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences.Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
机译:评价了新型烷基化的二肽美法兰基-对-L-氟苯丙氨酸乙酯(J1)在小鼠中的急性毒性和抗肿瘤活性,以美法兰为参考。为了确定用于疗效研究的安全且可耐受的剂量,使用14天的时间表(最多4剂)监测尾静脉静脉注射后的急性毒性。最高测试剂量为25微摩尔/千克,被认为接近该水平,对体重增加影响不大,但对血液学参数影响较大。 Melphalan和J1表现出同等毒性,无统计学显着性差异。随后,将小鼠中空纤维模型用于皮下植入含有人类肿瘤细胞的纤维。三种不同的人类肿瘤细胞系以及两种原发性人类肿瘤细胞样本(卵巢癌和慢性淋巴白血病)被用作肿瘤模型。与安慰剂和美法仑治疗组相比,在所测试的剂量水平下,T细胞白血病CCRF-CEM和小细胞肺癌NCI-H69肿瘤细胞生长以及对J1的存活率均显着且统计学上显着降低。在原发性卵巢癌细胞中,仅J1处理可导致明显的肿瘤消退(净细胞杀伤)。总而言之,结果表明,尽管血液循环的预期时间很短,但先前J1研究的有希望的体外数据似乎可以转化为体内情况。与美法仑相比,相同剂量的烷基化单元J1在小鼠中空纤维模型中更具活性,但显示出相似的一般毒性。

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