Inhibition of ribonucleotide reductase, DNA synthesis, and L1210 leukemia by guanazole.
Inhibition of ribonucleotide reductase, DNA synthesis, and L1210 leukemia by guanazole.
复制标题
胍唑抑制核糖核苷酸还原酶、DNA 合成和 L1210 白血病。
作者：
R. W. Brockman;S. Shaddix;Laster Wr;Frank M. Schabel
在体内L1210白血病细胞中，发现胍唑（3，5-二氨基-1，2，4-三唑; NSC 1895）抑制腺嘌呤、次黄嘌呤和尿苷掺入DNA的程度远大于掺入RNA的程度。胸苷掺入DNA的抑制与伴随的积累的dTTP在L1210细胞。亮氨酸掺入蛋白质没有受到抑制。甲酸-14 C嘌呤核苷酸的掺入被胍唑部分抑制，并伴随着减少标记的核酸，对DNA合成的影响比对RNA更明显。在培养的人表皮样癌细胞中获得了类似的结果。胍唑抑制人表皮样癌细胞酶制剂催化的核糖核苷酸还原为脱氧核糖核苷酸。胍唑对DNA合成和核糖核苷酸还原酶的影响与羟基脲相似。胍唑抗L1210白血病的实验评价表明，剂量方案和L1210细胞植入途径是药物疗效的决定因素。当腹膜内植入10 × 10 - 5个L1210细胞后，每3小时腹膜内给予胍唑8次，持续至少3个疗程（第1、5和9天）时，大量小鼠存活。在这方面，该化合物也类似于羟基脲。
Summary Guanazole (3,5-diamino-1,2,4-triazole; NSC 1895) was found to inhibit the incorporation of adenine, hypoxanthine, and uridine into DNA to a much greater extent than into RNA in L1210 leukemia cells in vivo . Thymidine incorporation into DNA was inhibited with concomitant accumulation of dTTP in L1210 cells. Leucine incorporation into protein was not inhibited. The incorporation of formate- 14 C into purine nucleotides was partially inhibited by guanazole and was accompanied by decreased labeling of nucleic acids; the effect on DNA synthesis was more pronounced than that on RNA. Similar results were obtained in human epidermoid carcinoma cells in culture. Guanazole inhibited the reduction of ribonucleotides to deoxyribonucleotides catalyzed by enzyme preparations from human epidermoid carcinoma cells. The effects of guanazole on DNA synthesis and on ribonucleotide reductase were similar to those of hydroxyurea. The experimental evaluation of guanazole against L1210 leukemia showed that dosage scheduling and route of implantation of L1210 cells were determining factors in the efficacy of the drug. When guanazole was given i.p. every 3 hr for 8 doses for a least 3 courses of treatment (Days 1, 5, and 9) after i.p. implantation of 10 5 L1210 cells, significant numbers of mice survived. In this respect also, the compound was similar to hydroxyurea.