3-Aryl-2-quinolone derivatives: synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration.
Among 25 3-aryl-2-quinolone derivatives synthesized, the antitumor activity of some of them was characterized both in vitro and in vivo. In this series, no compound appeared to be cytotoxic in vitro, as was known by the colorimetric MTT assay carried out on 12 distinct human cancer cell lines obtained from the American Type Culture Collection. Indeed, the concentration values decreasing the growth of the 12 cell lines by at least 50% (IC(50) index) were always higher than 10(-5) M. We then made use of a computer-assisted phase-contrast videomicroscopy system to quantitatively determine in vitro the level of migration of living MCF-7 human breast cancer cells. For example, at 10(-7) M, compounds 7, 13, 16, and 28 markedly decreased the migration level of these MCF-7 human breast cancer cells. The in vivo determination of the maximum tolerated dose showed that all compounds tested were definitively nontoxic. When the nontoxic, antimigratory compound 16 was combined with either doxorubicin or etoposide, two cytotoxic compounds routinely used in the clinic, this led to additive in vivo benefits from this treatment (as compared to individual administrations of the drugs) when the MXT mouse mammary adenocarcinoma was used. Thus, nontoxic antimigratory compounds, including the 2-quinolone derivatives synthesized here, can actually improve the efficiency of antitumor treatment when combined with conventional cytotoxic agents.
Joseph
Benoît
B
Institut de Chimie Organique et Analytique UMR-CNRS 6005, Université d'Orléans, BP 6759, 45067 Orléans Cedex 2, France. benoit.joseph@univ-orleans.fr
Darro
Francis
F
Béhard
Aurélie
A
Lesur
Brigitte
B
Collignon
Françoise
F
Decaestecker
Christine
C
Frydman
Armand
A
Guillaumet
Gérald
G
Kiss
Robert
R
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008858:Microscopy, Phase-Contrast; D009368:Neoplasm Transplantation; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015363:Quinolones; D013777:Tetrazoles; D005047:Etoposide; D004317:Doxorubicin; C458042:1-(2-(1H-1,2,3,4-tetrazol-5-yl)ethyl)-5,7-dimethoxy-3-(4-methoxyphenyl)-1,2-dihydro-2-quinolinone