<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec id="j_raon-2017-0034_s_101">
<h3>Background</h3>
<p>Cisplatin is used in cancer therapy, but its side effects and acquired resistance to cisplatin have led to the synthesis and evaluation of new platinum compounds. Recently, the synthesized platinum compound <italic>trans</italic>-[PtCl<sub>2</sub>(3-Hmpy)<sub>2</sub>] (3-Hmpy = 3-hydroxymethylpyridine) (compound <bold>2</bold>) showed a considerable cytotoxic and antitumour effectiveness. To improve compound <bold>2</bold> cytotoxicity <italic>in vitro</italic> and antitumour effectiveness <italic>in vivo</italic>, electroporation was used as drug delivery approach to increase membrane permeability (electrochemotherapy).</p></sec>
<sec id="j_raon-2017-0034_s_102">
<h3>Materials and methods</h3>
<p><italic>In vitro</italic>, survival of sarcoma cells with different intrinsic sensitivity to cisplatin (TBLCl2 sensitive, TBLCl2Pt resistant and SA-1 moderately sensitive) was determined using a clonogenic assay after treatment with compound <bold>2</bold> or cisplatin electrochemotherapy. <italic>In vivo</italic>, the antitumour effectiveness of electrochemotherapy with compound <bold>2</bold> or cisplatin was evaluated using a tumour growth delay assay. In addition, platinum in the serum, tumours and platinum bound to the DNA in the cells were performed using inductively coupled plasma mass spectrometry.</p></sec>
<sec id="j_raon-2017-0034_s_103">
<h3>Results</h3>
<p><italic>In vitro</italic>, cell survival after treatment with compound <bold>2</bold> electrochemotherapy was significantly decreased in all tested sarcoma cells with different intrinsic sensitivity to cisplatin (TBLCl2 sensitive, TBLCl2Pt resistant and SA-1 moderately sensitive). However, this effect was less pronounced compared to cisplatin. Interestingly, the enhancement factor (5-fold) of compound <bold>2</bold> cytotoxicity was equal in cisplatin-sensitive TBLCl2 and cisplatin-resistant TBLCl2Pt cells. <italic>In vivo</italic>, the growth delay of subcutaneous tumours after treatment with compound <bold>2</bold> electrochemotherapy was lower compared to cisplatin. The highest antitumour effectiveness after cisplatin or compound <bold>2</bold> electrochemotherapy was obtained in TBLCl2 tumours, resulting in 67% and 11% of tumour cures, respectively. Compound <bold>2</bold> induced significantly smaller loss of animal body weight compared to cisplatin. Furthermore, platinum amounts in tumours after compound <bold>2</bold> or cisplatin electrochemotherapy were approximately 2-fold higher compared to the drug treatment only, and the same increase of platinum bound to DNA was observed.</p></sec>
<sec id="j_raon-2017-0034_s_104">
<h3>Conclusions</h3>
<p>The obtained results <italic>in vitro</italic> and <italic>in vivo</italic> suggest compound <bold>2</bold> as a potential antitumour agent in electrochemotherapy.</p></sec>
</abstract>

Background
Cisplatin is used in cancer therapy, but its side effects and acquired resistance to cisplatin have led to the synthesis and evaluation of new platinum compounds. Recently, the synthesized platinum compound trans-[PtCl2(3-Hmpy)2] (3-Hmpy = 3-hydroxymethylpyridine) (compound 2) showed a considerable cytotoxic and antitumour effectiveness. To improve compound 2 cytotoxicity in vitro and antitumour effectiveness in vivo, electroporation was used as drug delivery approach to increase membrane permeability (electrochemotherapy).

Materials and methods
In vitro, survival of sarcoma cells with different intrinsic sensitivity to cisplatin (TBLCl2 sensitive, TBLCl2Pt resistant and SA-1 moderately sensitive) was determined using a clonogenic assay after treatment with compound 2 or cisplatin electrochemotherapy. In vivo, the antitumour effectiveness of electrochemotherapy with compound 2 or cisplatin was evaluated using a tumour growth delay assay. In addition, platinum in the serum, tumours and platinum bound to the DNA in the cells were performed using inductively coupled plasma mass spectrometry.

Results
In vitro, cell survival after treatment with compound 2 electrochemotherapy was significantly decreased in all tested sarcoma cells with different intrinsic sensitivity to cisplatin (TBLCl2 sensitive, TBLCl2Pt resistant and SA-1 moderately sensitive). However, this effect was less pronounced compared to cisplatin. Interestingly, the enhancement factor (5-fold) of compound 2 cytotoxicity was equal in cisplatin-sensitive TBLCl2 and cisplatin-resistant TBLCl2Pt cells. In vivo, the growth delay of subcutaneous tumours after treatment with compound 2 electrochemotherapy was lower compared to cisplatin. The highest antitumour effectiveness after cisplatin or compound 2 electrochemotherapy was obtained in TBLCl2 tumours, resulting in 67% and 11% of tumour cures, respectively. Compound 2 induced significantly smaller loss of animal body weight compared to cisplatin. Furthermore, platinum amounts in tumours after compound 2 or cisplatin electrochemotherapy were approximately 2-fold higher compared to the drug treatment only, and the same increase of platinum bound to DNA was observed.

Conclusions
The obtained results in vitro and in vivo suggest compound 2 as a potential antitumour agent in electrochemotherapy.

<italic>In vitro</italic> and in <italic>vivo</italic> evaluation of electrochemotherapy with <italic>trans</italic>-platinum analogue trans-[PtCl<sub>2</sub>(3-Hmpy)<sub>2</sub>]

Radiology and Oncology

This work is licensed under the Creative Commons Attribution 4.0 International License.

 and in  evaluation of electrochemotherapy with -platinum analogue trans-[PtCl(3-Hmpy)]

Background
Cisplatin is used in cancer therapy, but its side effects and acquired resistance to cisplatin have led to the synthesis and evaluation of new...

In vitro and in vivo evaluation of electrochemotherapy with trans-platinum analogue trans-[PtCl₂(3-Hmpy)₂]

Article Category: Research Article

Publicado en línea: 14 sept 2017

Páginas: 295 - 306

Recibido: 20 jul 2017

Aceptado: 04 ago 2017

DOI: https://doi.org/10.1515/raon-2017-0034

© 2017 Simona Kranjc, Maja Cemazar, Gregor Sersa, Janez Scancar, Sabina Grabner

This work is licensed under the Creative Commons Attribution 4.0 International License.

In vitro and in vivo evaluation of electrochemotherapy with trans-platinum analogue trans-[PtCl2(3-Hmpy)2]

Article Category: Research Article

Publicado en línea: 14 sept 2017

Páginas: 295 - 306

Recibido: 20 jul 2017

Aceptado: 04 ago 2017

DOI: https://doi.org/10.1515/raon-2017-0034

© 2017 Simona Kranjc, Maja Cemazar, Gregor Sersa, Janez Scancar, Sabina Grabner

This work is licensed under the Creative Commons Attribution 4.0 International License.

In vitro and in vivo evaluation of electrochemotherapy with trans-platinum analogue trans-[PtCl₂(3-Hmpy)₂]