Abstract
The ruthenium complexestrans-dichlorotetrakisdimethylsulfoxide ruthenium(II) (trans-Ru), imidazoliumtrans-imidazoletetrachlororuthenate (ICR), sodiumtrans-tetramethylensulfoxideisoquinolinetetrachlororuthenate (TEQU), and imidazoliumtrans-imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A) are tested in vitro by short exposure of MCF-7, LoVo, KB, and TS/A tumor cells to 10−4 M concentration, and in vivo on Lewis lung carcinoma by a daily i.p. treatment for 6 consecutive days using equitoxic and maximum tolerated doses. NAMI-A 1) inhibited tumor cell invasion of matrigel, 2) induced a transient accumulation of cells in the G2-M phase, 3) did not modify in vitro cell growth, and 4) markedly reduced lung metastasis formation. TEQU showed significant cytotoxicity in vitro and was not antimetastatic in vivo. ICR and trans-Ru did not modify cell cycle distribution of in vitro tumor cells nor did they inhibit matrigel invasion; ICR was also devoid of antimetastasis effects in vivo. Ruthenium uptake by tumor cells did account for in vitro cytotoxicity but not for other in vitro actions or for in vivo antimetastasis activity. The contemporary absence of cytotoxicity, associated to inhibition of matrigel crossing and to transient block in the premitotic G2-M phase, appears to be prerequisites for a ruthenium compound to show in vivo-selective antimetastasis effect. The validation of this model for other classes of compounds will allow an understanding of the combined weight of the above-mentioned phenomena for tumor metastasis growth and control.
Footnotes
-
Send reprint requests to: G. Sava, Callerio Foundation Onlus, via A. Fleming 22-31, 34127 Trieste, Italy. E-mail:g.sava{at}callerio.org
- Abbreviations:
- NAMI-A
- imidazoliumtrans-imidazoledimethylsulfoxidetetrachlororuthenate
- trans-Ru
- trans-dichlorotetrakisdimethylsulfoxide ruthenium(II)
- ICR
- imidazoliumtrans-imidazoletetrachlororuthenate
- TEQU
- sodiumtrans-tetramethylensulfoxideisoquinolinetetrachlororuthenate
- FBS
- fetal bovine serum
- MTT
- 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide
- TMAH
- tetramethylammoniumhydroxide
- Received June 5, 2000.
- Accepted August 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|