Primary Tumor, Lung and Kidney Retention and Antimetastasis Effect of NAMI-A Following Different Routes of Administration

Abstract

Imidazolium-trans-dimethylsulfoxideimidazoletetrachlororuthenate (NAMI-A) is a ruthenium compound effective on solid tumor metastases. In this study, we evaluated the effects of different routes of administration of NAMI-A on the distribution to primary tumor, lungs and kidneys in BD2F1 hybrids with Lewis lung carcinoma or in CBA inbred mice with MCa mammary carcinoma. NAMI-A concentration and the percentage of cumulative dose (%Dtot) retained in these tissues is independent of the animal strain and of the tumor model used. Also the presence of the tumor does not change the distribution of NAMI-A in the lungs and in the kidneys. A dose-dependent antimetastatic effect is evident with intraperitoneal (i.p.) treatments at three different doses. Treatment of tumor bearing mice with NAMI-A administered i.p., per os or by aerosol showed a similar effect on lung metastases, although the concentration of ruthenium reached in the lungs was markedly different. On the basis of the data obtained, we can conclude that the antimetastatic effects are related to the amount of NAMI-A administered, rather than to the lung's concentration of the compound.

Systematic Design of a Targeted Organometallic Antitumour Drug in Pre-clinical Development

“…[18] Imidazolium trans-[tetrachloro (DMSO)(imidazole)ruthenate(III)], NAMI-A, binds within minutes to plasma proteins, [19] inhibits lung metastases formation and reduces metastases weight without affecting the primary tumour. [20] Indeed, both in vitro and in vivo data appear to exclude DNA as the primary target, in line with the observation that the binding of NAMI-A to DNA is much weaker than platinum complexes. [21] KP1019 and NAMI-A are both progressing through clinical trials.…”

Thirty Years of the Drug Candidate NAMI‐A and the Myths in the Field of Ruthenium Anticancer Compounds: A Personal Perspective

“…The cellular effects of NAMI‐A that typically correlate with the in vivo antimetastatic activity were detected at doses 100 to 1000 times below those inducing cytotoxicity , , . Preclinical studies demonstrated that the effect of NAMI‐A in metastasis inhibition was independent of the administered dose, both in terms of frequency and in terms of route of administration . Finally, in the clinical studies the cases of stable disease (phase I) and partial response (phase I/II) were all found at the lowest doses of NAMI‐A.…”

Adding diversity to ruthenium(II)–arene anticancer (RAPTA) compounds via click chemistry: The influence of hydrophobic chains

“…1). Both compounds behave quite differently to cisplatin; NAMI-A inhibits growth of metastatic tumours [8], while KP1019 is active in colorectal tumours where cisplatin exhibits limited activity [9]. Protein binding, especially to transport proteins, appears to be essential for the modes of action of certain ruthenium anticancer agents [10].…”