4 ' -epi-doxorubicin阿霉素的新模拟:临床前和临床数据的初步概述。
文章的细节
-
引用
复制到剪贴板 -
Ganzina F
4 ' -epi-doxorubicin阿霉素的新模拟:临床前和临床数据的初步概述。
癌症治疗牧师1983年3月,10(1):22页。
- PubMed ID
-
6342772 (在PubMed]
- 文摘
-
4 ' -epi-doxorubicin (4 ' -epi-DX)是一种新型蒽环霉素抗生素。它不同于阿霉素(DX)的差向异构化作用哦组位置4的合成了氨基糖基,和为了找到代理与优越的治疗指数母体化合物阿霉素(DX)。4 ' -epi-doxorubicin与DNA结合,抑制核酸合成和功能。在几个实验4的抗肿瘤活性-epi-DX肿瘤(白血病1210 L, 388页,白血病,总值180肉瘤腹水的和固体,影响他乳房癌)类似于DX。然而,4 ' -epi-doxorubicin抗肿瘤活性比阿霉素在路易斯肺癌,MS-2肉瘤肺转移,在无胸腺的老鼠和人类黑色素瘤。慢性毒性研究中没有定性差异4 ' -epi-DX DX;然而,定量4 ' -epi-DX与其说是有毒的。在不同实验模型4 ' -epi-DX cardiotoxic已被证明是低于其母体化合物。兔子在慢性毒性研究,组织病理结果显示相同的模式这两种药物的毒性,但少-epi-DX标有4”。分布在小鼠肿瘤的研究显示,较低浓度的4 ' -epi-DX在心脏,脾脏和肾脏; the hepatobiliary metabolism and excretion of 4'-epi-DX investigated in the rat, indicated that the new analogue was more extensively metabolized than the parent compound. Pharmacokinetics of 4'-epi-DX in humans showed a multiexponential decrease of plasma levels; the same pattern was observed for the metabolite 13-OH epidoxorubicinol but with lower concentrations than the unchanged drug. A high plasma clearance (0.9-1.41/min), a terminal half-life of about 30-40 hr and a large volume of distribution were the main pharmacokinetic characteristics of 4'-epi-DX. A reduction of the dose appears to be appropriate in patients with liver function impairment. Phase II studies with 4'-epi-DX have indicated that the drug produces a pattern of acute toxicity, including acute cardiac toxicity, qualitatively similar to that of DX at identical doses but quantitatively lower, with particular regard to leukopenia and gastrointestinal toxicity. The range of single active doses is between 60 and 90 mg/m2, the most frequently employed doses schedules being 75 or 90 mg/m2 i.v. every 3 weeks. 4'-epi-DX has shown activity in a variety of tumors such as breast carcinoma, soft tissues sarcomas, NH lymphomas, leukemias, ovarian cancer and gastric cancer. Preliminary evidence of activity has been found in melanoma, rectal cancer and pancreatic cancer suggesting a broad spectrum of activity. As to chronic cardiac toxicity up to now only 2 mild to moderate and reversible CHF have been observed at doses of 1120 and 1235 mg/m2 in about 700 treated patients. Specific and comparative studies are in progress: preliminary findings from a randomized comparison of 4'-epi-DX vs DX in breast cancer indicated that 4'-epi-DX may have a lower cumulative cardiotoxicity.