Abstract
Intratumor (i.t.) injection of 35 mg/kg/day NAMI-A for six consecutive days to CBA mice bearing i.m. implants of MCa mammary carcinoma reduces primary tumor growth and particularly lung metastasis formation, causing 60% of animals to be free of macroscopically detectable metastases. The i.t. treatment allows study of the effects of NAMI-A on in vivo tumor cells exposed to millimolar concentrations for a relatively prolonged time. Under these conditions, NAMI-A reduces the number of CD44+ tumor cells and changes tumor cell phenotype to a lower aggressive behavior, as shown by scanning electron microscopy analysis. On primary tumor site, NAMI-A causes unbalance between 2n and aneuploid cells in favor of lymphocytes. Furthermore, in tumor tissue, nitric oxide production is increased and active matrix metalloproteinase 9 is decreased, and these effects are accompanied by a reduced hemoglobin concentration. These data are in agreement with the reduction of tumor invasion and metastasis and suggest the therapeutic usefulness of NAMI-A in neoadjuvant or tumor reduction treatments for preventing metastasis formation. These data further stress the usefulness of intratumor treatments as experimental preclinical model for studying in vivo the mechanism of tumor cell interactions after prolonged exposure to ruthenium-based compounds to be developed for metastasis inhibition.
Footnotes
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This work was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (prot.2001053898_004, Pharmacological mechanisms of the antimetastatic activity of metal-based drugs) and in the framework of COST D200005/01 action.
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DOI: 10.1124/jpet.104.066175.
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ABBREVIATIONS: NAMI-A, imidazolium trans-imidazoledimethylsulfoxide tetrachlororuthenate, ImH[trans-RuCl4(DMSO)Im]; i.t., intratumor; TIL, tumor infiltrating lymphocyte; HA, hyaluronic acid; DMSO, dimethyl sulfoxide; MCa, murine mammary carcinoma; MoAb, monoclonal antibody; PI, propidium iodide; PBS-NaN3-BSA, phosphate-buffered saline-sodium azide-bovine serum albumin; PE, phycoerytreine; SEM, scanning electron micrograph.
- Received January 27, 2004.
- Accepted April 6, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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