Stereo (C7)-dependent topoisomerase II inhibition and tumor growth suppression by a new quinolone, BO-2367
| Autor: | Eiichi Mano, Masae Kurama, Tomoko Iguchi, Tomoko Yoshinari, N. Tanaka, Hiroharu Arakawa, Nakagawa Susumu, Akira Okura |
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| Rok vydání: | 1993 |
| Předmět: |
Cancer Research
Quinolone medicine.drug_class Mice Inbred Strains Biology Quinolones DNA gyrase Article Mice Anti-Infective Agents medicine Animals Topoisomerase II Inhibitors Leukemia L1210 Etoposide DNA cleavage DNA Superhelical Leukemia P388 Topoisomerase Carcinoma Stereoisomerism DNA Neoplasm biology.organism_classification Topoisomerase II DNA Topoisomerases Type II Oncology Biochemistry Anticancer agent Enzyme Induction Colonic Neoplasms biology.protein DNA supercoil L1210 cells Female Topoisomerase-II Inhibitor Drug Screening Assays Antitumor Micrococcus luteus medicine.drug Fluoroquinolones |
| Zdroj: | Japanese Journal of Cancer Research : Gann |
| ISSN: | 0910-5050 |
| Popis: | A new antimicrobial quinolone (-)BO-2367, (-)-7-[(1R*, 2R*, 6R*)-2-amino-8-azabicyclo[4.3.0.]-non-3-en-8-yl]-1- cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, strongly inhibited both mammalian and bacterial topoisomerase II. The IC50 values of (-)BO-2367 against the DNA relaxation activity of L1210 topoisomerase II and the supercoiling activities of Escherichia coli gyrase and Micrococcus luteus gyrase were 3.8, 0.5, and 1 microM, respectively. This compound enhanced double-stranded DNA cleavage mediated by topoisomerase II not only with purified enzyme, but also with intact L1210 cells. All these activities of (-)BO-2367 were more than 2-fold stronger than those of VP-16. Intriguingly, (+)BO-2367, which has an enantiomeric substituent at the C7 position of (-)BO-2367, did not affect the activity of the mammalian topoisomerase II, while it inhibited E. coli gyrase. Intraperitoneal injection of (-)BO-2367 at 0.08 mg/kg increased the lifespan of CDF1 female mice bearing ascitic L1210 leukemia by 2.4 times, and subcutaneous injection at 1.25 mg/kg completely inhibited the growth of colon 26 carcinoma implanted subcutaneously. These results suggest that (-)BO-2367 is a potent antitumor agent which targets topoisomerase II. These enantiomers should be a useful tool for studying drug-topoisomerase II interactions. |
| Databáze: | OpenAIRE |
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