Nagasawa Hideko, Yamashita Mao, Mikamo Naoko, Shimamura Mariko, Oka Shigenori, Uto Yoshihiro, Hori Hitoshi
Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Minamijosanjima-cho 2-1, Tokushima 770-8506, Japan.
Comp Biochem Physiol A Mol Integr Physiol. 2002 May;132(1):33-40. doi: 10.1016/s1095-6433(01)00526-8.
For cancer therapy, hypoxia represents an important tumor specific target. Therefore we designed and synthesized antiangiogenic hypoxic cytotoxins as 'hypoxia modifiers'. They can be activated bioreductively in hypoxic cells to kill the oxygen-deficient tumor cells selectively and prevent their re-growth. The aromatic heterocycle di-N-oxides, tirapazamine (TPZ), TX-1102, and TX-402 inhibited growth of EMT6/KU cells, SAS/neo cells, and SAS/Trp248 cells (mutant p53 gene transformant) under hypoxic condition. They also induced apoptosis selectively at a dose of 10 microM each under hypoxic condition for 5 h. Their hypoxic cytotoxicities and apoptosis inducing activities were p53-independent because the activities in SAS/neo cells were almost similar to that in SAS/Trp248 cells. In angiogenesis inhibition assay using chick embryo chorioallantoic membrane (CAM), TPZ, TX-1102, TX-402 and TX-1033 showed 40, 25, 60 and 60% inhibition of angiogenesis each at a dose of 10 microg/CAM. On the other hand, the nitrosopyrimidine, TX-1041 had neither antiangiogenic activity nor cytotoxicity. Therefore the di-N-oxide group is thought to be required for the biological activities. TX-1102 was a potent antiangiogenic hypoxic cytotoxin inducing apoptosis p53-independently.
对于癌症治疗而言，缺氧是一个重要的肿瘤特异性靶点。因此，我们设计并合成了抗血管生成的缺氧细胞毒素作为“缺氧调节剂”。它们可在缺氧细胞中通过生物还原作用被激活，从而选择性地杀死缺氧的肿瘤细胞，并阻止其再次生长。芳香族杂环二氮氧化物替拉扎明（TPZ）、TX - 1102和TX - 402在缺氧条件下抑制了EMT6/KU细胞、SAS/neo细胞和SAS/Trp248细胞（突变型p53基因转化体）的生长。在缺氧条件下处理5小时，它们各自在10微摩尔的剂量下还能选择性地诱导细胞凋亡。它们的缺氧细胞毒性和诱导凋亡活性与p53无关，因为SAS/neo细胞中的活性与SAS/Trp248细胞中的活性几乎相似。在使用鸡胚绒毛尿囊膜（CAM）的血管生成抑制试验中，TPZ、TX - 1102、TX - 402和TX - 1033在10微克/CAM的剂量下分别显示出40%、25%、60%和60%的血管生成抑制率。另一方面，亚硝基嘧啶TX - 1041既没有抗血管生成活性也没有细胞毒性。因此，二氮氧化物基团被认为是这些生物活性所必需的。TX - 1102是一种强效的抗血管生成缺氧细胞毒素，可独立于p53诱导细胞凋亡。
