NAMI-A

NAMI-A and KP1019 are two ruthenium anticancer agents that have entered clinical trials.[1][2] Contrary to what can be found in some papers, "the nickname NAMI is not the acronym of “New Anticancer Metastasis Inhibitor”, but has a much more prosaic origin. It was created by a student as a short-form name of the chemical formula of the complex: “NA” comes from the symbol for sodium and “MI” from the word imidazole. The corresponding imidazolium salt was simply called NAMI-A to signify that it was an upgraded version of the prototype NAMI".[3]

NAMI-A
Clinical data
Routes of
administration		Intravenous
ATC code
  • None
Identifiers
CAS Number
UNII
Chemical and physical data
FormulaC8H15Cl4N4ORuS
Molar mass458.17 g·mol−1

NAMI-A and KP1019 are based primarily around the use of the metal ruthenium. Ruthenium is unknown to living systems, with a strong complex forming ability with numerous ligands.[4] Its partially filled 4d sub-shell allows it to form complexes that are useful for a wide variety of applications including catalysis, electronics, photochemistry, biosensors and anticancer drugs.[1][5] Ruthenium, unlike traditional platinum complexes such as cisplatin, shows greater resistance to hydrolysis and more selective action on tumors.

Background

New anti-tumor metastasis inhibitor or NAMI-A is a ruthenium based anti-cancer drug and is one of two ruthenium-based drugs that have entered clinical trials.[6]

NAMI-A is considered a pro-drug formulation that becomes active upon hydrolysis. At pH 7.4, a chloride is exchanged with a water molecule, which neutralizes the molecule’s -1 charge. Upon lower pH, imidazole is cleaved and replaced with water.[7]

NAMI-A dissociates differently based on pH (Sava et al., 2001).

Unlike cisplatin, a platinum based drug, it has been shown in-vivo that NAMI-A doesn’t inhibit primary tumor growth but decreases the speed at which metastasis occurs.[8] It has also been found that when compared to highly cytotoxic platinum compounds, NAMI-A is much less cytotoxic and has a differing mechanism of action.[9]

Preclinical trials

Several preclinical trials were conducted in different model systems.

In 2002, a study published by Vacca et al. showed that endothelial cells incubated with NAMI-A, were not able to proliferate but that NAMI-A didn't kill the cells that were already grown.[10]

One trial was done to test the efficacy of NAMI-A in female[11] grafted with MCa mammary carcinoma cells. It was determined that, NAMI-A showed very little toxicity yet managed to decrease the rate of metastasis. Perhaps most impressively is that, though NAMI-A is very sensitive to the environment, it is able to be effective over a range of conditions.[7]

Clinical trials

Clinical trials were conducted at the Netherlands Cancer Institute (NKI).

Phase I – monotherapy

Phase I trials were conducted on NAMI-A in patients with varying solid tumors 3 hrs a day, 5 days a week, for 3 weeks at varying doses. Drug was given intravenously with and without a port-a-cath. Several side effects were observed including:[12]

  • Mild hematologic toxicity - blood related toxicity
  • Nausea
  • Vomiting
  • Diarrhea
  • Stomatitis – inflammation of mouth and lips
  • Fatigue
  • Creatinine increase – common toxicity (CTC) grade 1 and 2 - High levels indicate kidney dysfunction
  • Fever
  • Sensitivity reactions to drug
  • Phlebitis at injection site
  • Blisters on hands and feet

Of the 24 patients in the study, 20 were evaluated for final results. At the end of the study, 19 of the 20 showed disease progression while 1 patient showed no progression.[12]

Due to these results, Phase II trials, using NAMI-A as a solo drug, were not pursued.

Phase I and II – combination therapy with gemcitabine

Due to negative results of the stand-alone Phase I trial, and knowledge that NAMI-A slows down progression of metastasis, and not growth of the initial tumor, Phase I & II trials were done using gemcitabine, a nucleoside analog that has shown to be successful in treating lung cancer.

Phase I trial

Phase I trials were done to determine the optimal and maximum tolerated dose (MTD)of NAMI-A as well as determining the pharmacokinetics of NAMI-A and gemcitabine administered jointly. This was accomplished by a dose escalation study. The minimal dosage was 300 mg/m2 on a 28-day schedule and the max dosage was 600 mg/m2 administered on a 21-day schedule. 32 patients were enrolled in the study all of which had a form of non-small cell lung cancer (NSCLC), a median age of 57, most diagnosed as level III & IV of disease progression.[12]

Phase II trial

Phase II trials were done to evaluate how NAMI-A in combination with gemcitabine impact cancer progression. 19 patients were added in addition to those from the phase I trial. Of the 27 patients evaluated for final results -15 showed anti-tumor activity, 10 showed stable disease progression for 6–10 weeks, and 1 patient exhibited a partial remission (PR) on the 300 mg/m2 for 21 days.

The patient who was observed to have a partial remission, occurred during the dose escalation phase I trial. In order to expand the trial, there needed to be at least one patient in the phase II trial that showed PR as the best response. Unfortunately, this did not occur. In addition, it was found that the results of NAMI-A in combination with gemcitabine, did not show improved results from studies done with gemcitabine alone.[12]

Due to these results, clinical trials were terminated.

References
  1. Kostova I (2006). "Ruthenium complexes as anticancer agents". Current Medicinal Chemistry. 13 (9): 1085–107. doi:10.2174/092986706776360941. PMID 16611086.
  2. Lentz F, Drescher A, Lindauer A, Henke M, Hilger RA, Hartinger CG, et al. (February 2009). "Pharmacokinetics of a novel anticancer ruthenium complex (KP1019, FFC14A) in a phase I dose-escalation study". Anti-Cancer Drugs. 20 (2): 97–103. doi:10.1097/CAD.0b013e328322fbc5. PMID 19209025. S2CID 38457574.
  3. Alessio E, Guo Z (September 28, 2016). "Thirty Years of the Drug Candidate NAMI-A and the Myths in the Field of Ruthenium Anticancer Compounds: A Personal Perspective". European Journal of Inorganic Chemistry. 2017 (12): 1549–1560. doi:10.1002/ejic.201600986.
  4. Gopal YN, Jayaraju D, Kondapi AK (April 1999). "Inhibition of topoisomerase II catalytic activity by two ruthenium compounds: a ligand-dependent mode of action". Biochemistry. 38 (14): 4382–8. doi:10.1021/bi981990s. PMID 10194357.
  5. Antonarakis ES, Emadi A (May 2010). "Ruthenium-based chemotherapeutics: are they ready for prime time?". Cancer Chemotherapy and Pharmacology. 66 (1): 1–9. doi:10.1007/s00280-010-1293-1. PMC 4020437. PMID 20213076.
  6. Alessio E, Messori L (2018). "Chapter 5. The Deceptively Similar Ruthenium(III) Drug Candidates KP1019 and NAMI-A have Different Actions. What Did We Learn in the Past 30 Years?". In Sigel A, Sigel H, Freisinger E, Sigel RK (eds.). Metallo-Drugs:Development and Action of Anticancer Agents. Metal Ions in Life Sciences. 18. Berlin: de Gruyter GmbH. pp. 141–170. doi:10.1515/9783110470734-010. ISBN 9783110470734. PMID 29394023.
  7. Sava G, Bergamo A, Zorzet S, Gava B, Casarsa C, Cocchietto M, et al. (February 2002). "Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A". European Journal of Cancer. 38 (3): 427–35. doi:10.1016/S0959-8049(01)00389-6. PMID 11818210.
  8. Sava G, Zorzet S, Turrin C, Vita F, Soranzo M, Zabucchi G, et al. (May 2003). "Dual Action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen" (PDF). Clinical Cancer Research. 9 (5): 1898–905. PMID 12738748.
  9. Bergamo A, Gagliardi R, Scarcia V, Furlani A, Alessio E, Mestroni G, Sava G (April 1999). "In vitro cell cycle arrest, in vivo action on solid metastasizing tumors, and host toxicity of the antimetastatic drug NAMI-A and cisplatin" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 289 (1): 559–64. PMID 10087050.
  10. Vacca A, Bruno M, Boccarelli A, Coluccia M, Ribatti D, Bergamo A, et al. (March 2002). "Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A". British Journal of Cancer. 86 (6): 993–8. doi:10.1038/sj.bjc.6600176. PMC 2364145. PMID 11953835.
  11. Lukashevich IS, Malkovský M, Schorlemmer HU, Bobé P, Artym J. "Mice, Inbred CBA". WikiGenes.
  12. Leijen S, Burgers SA, Baas P, Pluim D, Tibben M, van Werkhoven E, et al. (February 2015). "Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy". Investigational New Drugs. 33 (1): 201–14. doi:10.1007/s10637-014-0179-1. hdl:1874/314465. PMID 25344453. S2CID 27817700.
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