PRECLINICAL ANTITUMOR-ACTIVITY AND ANIMAL TOXICOLOGY STUDIES OF RHIZOXIN, A NOVEL TUBULIN-INTERACTING AGENT
PRECLINICAL ANTITUMOR-ACTIVITY AND ANIMAL TOXICOLOGY STUDIES OF RHIZOXIN, A NOVEL TUBULIN-INTERACTING AGENT
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DOI：
10.1093/oxfordjournals.annonc.a058334
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发表时间：
1992-11-01
影响因子：
50.5
通讯作者：
SCHWARTSMANN, G
中科院分区：
文献类型：
--
作者：
HENDRIKS, HR;PLOWMAN, J;SCHWARTSMANN, G
Rhizoxin是一种从植物病原真菌Rhizopus chinensis中分离得到的具有16个分子的抗真菌大环内酯。该化合物与微管蛋白结合，阻止微管形成，抑制有丝分裂。它在体内对各种临床前小鼠模型具有抗肿瘤活性，包括白血病和实体肿瘤模型，以及长春新碱和阿霉素耐药白血病系。在本研究中，在体外非常低浓度（+/- 10(-10)M）的人类肿瘤细胞系中观察到细胞毒活性，特别是对黑色素瘤、结肠癌、肾癌、非小细胞癌和小细胞肺癌。在小鼠P388和L1210小鼠白血病，实体瘤模型B16黑色素瘤和M5076肉瘤，以及9个人类实体瘤异种移植物中的5个：LOX黑色素瘤，MX-1乳腺癌中显示出体内抗肿瘤活性。非小细胞肺癌A549和小细胞肺癌LXFS 605和LXFS 650。在抗长春新碱耐药的P388白血病亚群和抗长春新碱的人小细胞肺癌LXFS 650的体内实验中证实了对长春新碱不存在交叉耐药。此外，根瘤素的抗肿瘤活性通过延长或重复给药而提高，表明有时间表依赖性。在动物毒理学研究中，观察到红细胞和白细胞数量的短暂变化，局部静脉炎，腹泻和生精停止。单次静脉注射后的LD10值为2.8 mg/kg （8.4 mg/m2）。临床I期研究的起始剂量为小鼠等效LD10的十分之一（0.84 mg/m2），在大鼠中被认为是安全的。根瘤素的抗肿瘤活性，它与微管蛋白的独特相互作用，以及在动物毒理学研究中缺乏不可控制的毒性作用，导致了根瘤素的临床试验选择。一项I期临床试验已经完成，显示白细胞减少、粘膜炎和腹泻是剂量限制性毒性。在一些病例中观察到静脉炎。这些毒性是通过动物毒理学研究预测出来的。此外，根瘤素在3例重度预处理的复发性乳腺癌患者中引起了轻微的反应。二期临床试验将很快在EORTC和CRC的框架内开始。
Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer. non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth ot the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats. The antitumour activity of rhizoxin, its unique interactions with tubulin and the absence of non-manageable toxic effects in the animal toxicological studies have led to rhizoxin's selection for clinical trials. A phase I clinical trial has been completed showing leukopenia, mucositis and diarrhea to be the dose-limiting toxicities. In some cases phlebitis was observed. These toxicities were predicted from the animal toxicological studies. In addition, rhizoxin caused minor responses in three heavily pretreated patients with recurrent breast cancer. Phase II clinical trials will start soon within the framework of the EORTC and CRC.