In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin.

Abstract

The effects of NAMI-A (imidazolium trans-imidazoledimethyl sulfoxide-tetrachlororuthenate) are compared with cisplatin on tumor cells cultured in vitro at doses of 1 to 100 microM 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.

• Authors: A Bergamo, R Gagliardi, V Scarcia, A Furlani, E Alessio, G Mestroni, G Sava
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 289 Issue 1 Pg. 559-64 (Apr 1999) ISSN: 0022-3565 [Print] United States
• PMID: 10087050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Organometallic Compounds
• Rhodamines
• Ruthenium Compounds
• imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
• lissamine rhodamine B
• Propidium
• Cisplatin
• Dimethyl Sulfoxide

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Cisplatin (pharmacology, toxicity)
• DNA, Neoplasm (biosynthesis, drug effects)
• Dimethyl Sulfoxide (analogs & derivatives, pharmacology, toxicity)
• Flow Cytometry
• Humans
• KB Cells
• Lung Neoplasms (drug therapy, pathology, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Neoplasm Transplantation
• Organometallic Compounds (pharmacology, toxicity)
• Propidium
• Rhodamines
• Ruthenium Compounds
• Tumor Cells, Cultured