Modulation of Activity of Known Cytotoxic Ruthenium(III) Compound (KP418) with Hampered Transmembrane Transport in Electrochemotherapy In Vitro and In Vivo
- 238 Downloads
To increase electrochemotherapy (ECT) applicability, the effectiveness of new drugs is being tested in combination with electroporation. Among them two ruthenium(III) compounds, (imH)[trans-RuCl4(im)(DMSO-S)] (NAMI-A) and Na[trans-RuCl4(ind)2] (KP1339), proved to possess increased antitumor effectiveness when combined with electroporation. The objective of our experimental work was to determine influence of electroporation on the cytotoxic and antitumor effect of a ruthenium(III) compound with hampered transmembrane transport, (imH)[trans-RuCl4(im)2] (KP418) in vitro and in vivo and to determine changes in metastatic potential of cells after ECT with KP418 in vitro. In addition, platinum compound cisplatin (CDDP) and ruthenium(III) compound NAMI-A were included in the experiments as reference compounds. Our results show that electroporation leads to increased cellular accumulation and cytotoxicity of KP418 in murine melanoma cell lines with low and high metastatic potential, B16-F1 and B16-F10, but not in murine fibrosarcoma cell line SA-1 in vitro which is probably due to variable effectiveness of ECT in different cell lines and tumors. Electroporation does not potentiate the cytotoxicity of KP418 as prominently as the cytotoxicity of CDDP. We also showed that the metastatic potential of cells which survived ECT with KP418 or NAMI-A does not change in vitro: resistance to detachment, invasiveness, and re-adhesion of cells after ECT is not affected. Experiments in murine tumor models B16-F1 and SA-1 showed that ECT with KP418 does not have any antitumor effect while ECT with CDDP induces significant dose-dependent tumor growth delay in the two tumor models used in vivo.
KeywordsKP418 Electrochemotherapy Ruthenium Metastatic potential In vitro In vivo
The authors acknowledge the financial support received from the State budget by the Slovenian Research Agency (ARRS) for programmes No. P1-0175, P2-0249, P3-0003, project J1-4131 and junior researcher grants for R.H. The authors would also like to acknowledge that all the experimental work related to metastatic potential of cells was performed at the Callerio Fundatione in Trieste under the supervision of dr. Gianni Sava and dr. Alberta Bergamo and with the help of their researches. The authors are also thankful to Dr. M. Jakupec (University of Vienna) for critical reading of the manuscript. This work was supported by COST D39 and COST CM1105, in particular by a short-term scientific mission for R.H.
- Cemazar M, Miklavcic D, Vodovnik L, Jarm T, Rudolf Z, Stabuc B, Cufer T, Sersa G (1995) Improved therapeutic effect of electrochemotherapy with cisplatin by intratumoral drug administration and changing of electrode orientation for electropermeabilization on EAT tumor model in mice. Radiol Oncol 29:121–127Google Scholar
- Edhemovic I, Gadzijev EM, Brecelj E, Miklavcic D, Kos B, Zupanic A, Mali B, Jarm T, Pavliha D, Marcan M, Gasljevic G, Gorjup V, Music M, Pecnik Vavpotic T, Cemazar M, Snoj M, Sersa G (2011) Electrochemotherapy: a new technological approach in treatment of metastases in the liver. Technol Cancer Res Treat 10:475–485PubMedCentralPubMedGoogle Scholar
- Heller R, Gilbert R, Jaroszeski MJ (2000) Clinical trials for solid tumors using electrochemotherapy. In: Electrochemotherapy, Electrogenetherapy, and Transdermal Drug Delivery. Electrically Mediated Delivery of Molecules to Cells. Jaroszeski MJ, Heller R and Gilbert R (eds.). New Jersey: Humana Press, pp. 137-156Google Scholar
- Marty M, Sersa G, Garbay JR, Gehl J, Collins CG, Snoj M, Billard V, Geertsen PF, Larkin JO, Miklavcic D (2006) Electrochemotherapy—an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. Eur J Cancer (Suppl 4): 3-13Google Scholar
- Mir LM, Gehl J, Sersa G, Collins CG, Garbay JR, Billard V, Geertsen PF, Rudolf Z, O’Sullivan GC, Marty M (2006) Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or CDDP administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or non-invasive electrodes. Eur J Cancer 4:14–25CrossRefGoogle Scholar
- Sava G, Zorzet S, Turrin C, Vita F, Soranzo MR, Zabucchi G, Cocchietto M, Bergamo A, DiGiovine S, Pezzoni G, Sartor L, Garbisa S (2003) Dual action of NAMI-A in inhibition of solid tumor metastasis: selective targeting of metastatic cells and binding to collagen. Clin Cancer Res 9:1898–1905PubMedGoogle Scholar
- Speelmans G, Sips WHHM, Grisel RJH, Staffhorst RWHM, Fichtinger-Schepman AMJ, Reedijk J, de Kruijff B (1996) The interaction of the anti-cancer drug cisplatin with phospholipids is specific for negatively charged phospholipids and takes place at low chloride ion concentration. Biochim Biophys Acta 1283:60–66CrossRefPubMedGoogle Scholar
- Spugnini EP, Citro G, Porrello A (2005) Rational design of new electrodes for electrochemotherapy. J ExpClin Cancer Res 24(2):245–254Google Scholar
- Zorzet S, Bergamo A, Cocchietto M, Sorc A, Gava B, Alessio E, Iengo E, Sava G (2000) Lack of in vitro cytotoxicity, associated to increased G2-M cell fraction and inhibition of matrigel invasion, may predict in vivo-selective antimetastasis activity of ruthenium complexes. JPET 295(3):927–933Google Scholar