Abstract
The effects of NAMI-A (imidazoliumtrans-imidazoledimethyl sulfoxide-tetrachlororuthenate) are compared with cisplatin on tumor cells cultured in vitro at doses of 1 to 100 μM and on tumor metastases in vivo at maximum tolerated doses. Using mouse tumors that metastasize to the lungs, NAMI-A given i.p. for 6 consecutive days at 35 mg/kg/day, was effective independently of the tumor line being treated and of the stage of metastasis growth. Conversely, cisplatin (2 mg/kg/day for 6 days) was as effective as NAMI-A on MCa mammary carcinoma and TS/A adenocarcinoma and less effective than NAMI-A on Lewis lung carcinoma. Cisplatin reduced body weight gain and spleen weight during treatment and was much more toxic than NAMI-A on liver sinusoids, kidney tubules, and lung epithelium. In vitro NAMI-A caused a transient cell cycle arrest of tumor cells in the premitotic G2/M phase, whereas cisplatin caused a progressive dose-dependent disruption of cell cycle phases. Correspondingly, NAMI-A did not modify cell growth, whereas cisplatin caused a dose-dependent reduction of cell proliferation, as determined by sulforhodamine B test. Thus, NAMI-A, unlike cisplatin, is a potent agent for the treatment of solid tumor metastases as well as when these tumor lesions are in an advanced stage of growth. NAMI-A is endowed with a mechanism of action unrelated to direct tumor cell cytotoxicity, and such mechanism of action is responsible for a reduced host toxicity.
Footnotes
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Send reprint requests to: G. Sava, Callerio Foundation, via A. Fleming 22-31, 34127 Trieste, Italy. E-mail:gsava{at}fc.univ.trieste.it
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↵1 This work was done with contributions from Ministero dell’Universitá e della Ricerca Scientifica e Technologica (60%) and Fondazione CRTrieste and was developed under the European Economic Community COST D8 Action.
- Abbreviations:
- NAMI-A
- imidazoliumtrans-imidazoledimethyl sulfoxide-tetrachlororuthenate
- NAMI
- sodium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate
- cisplatin
- cis-dichlorodiammine platinum(II)
- SRB
- sulphorhodamine B
- Received August 18, 1998.
- Accepted November 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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