Cisplatin – A more Efficient Drug in Combination with Radionuclides?

Abstract

Aim The combination of conventional chemotherapeutic drugs with radionuclides or external radiation is discussed for a long period of time. The major advantage of a successful combination therapy is the reduction of severe side effects by decreasing the needed dose and simultaneously increasing therapeutic efficiency.

Methods In this study, pUC19 plasmid DNA was incubated with the cytostatic drug cisplatin and additionally irradiated with ^99mTc, ¹⁸⁸Re and ²²³Ra. To verify the contribution of possibly excited platinum atoms to the emission of Auger electrons we determined DNA damages, such as single- and double strand breaks.

Results The threshold concentration value of cisplatin, which was tolerated by pUC19 plasmid DNA was determined to be 18–24 nM. Nevertheless, even at higher dose values (>100 Gy) and simultaneous incubation of cisplatin to 200 ng plasmid DNA, no significant increase in the number of induced single- and double-strand breaks was obtained, compared to the damage solely caused by the radionuclides.

Conclusion We thereby conclude that there is no direct dependence of the mechanism of strand break induction to the absence or presence of platinum atoms attached to the DNA. Reported increasing DNA damages in therapy approaches on a cellular level strongly depend on the study design and are mainly influenced by repair mechanisms in living cells. Nevertheless, the use of radioactive cisplatin, containing the Auger electron emitter ¹⁹¹Pt, ^193mPt or ^195mPt, is a bright prospect for future therapy by killing tumor cells combining two operating principles: a cytostatic drug and a radiopharmaceutical at the same time.

Zusammenfassung

Ziel Die Kombination herkömmlicher Chemotherapeutika mit Radionukliden oder externer Bestrahlung wird seit Langem diskutiert. Der große Vorteil einer erfolgreichen Kombinationstherapie ist die Reduzierung schwerer Nebenwirkungen durch Verringerung der benötigten Dosis bei gleichzeitiger Erhöhung der therapeutischen Effizienz.

Methoden In dieser Studie wurde pUC19-Plasmid-DNA mit dem Zytostatikum Cisplatin inkubiert und zusätzlich mit ^99mTc, ¹⁸⁸Re und ²²³Ra bestrahlt. Um den Beitrag möglicherweise angeregter Platinatome zur Emission von Auger-Elektronen zu überprüfen, bestimmten wir DNA-Schäden wie Einzel- und Doppelstrangbrüche.

Ergebnisse Als Schwellenkonzentrationswert von Cisplatin, der von pUC19-Plasmid-DNA toleriert wurde, wurde 18–24 nM bestimmt. Dennoch wurde selbst bei höheren Dosiswerten (>100Gy) und gleichzeitiger Inkubation von Cisplatin mit 200ng Plasmid-DNA keine signifikante Erhöhung der Zahl der induzierten Einzel- und Doppelstrangbrüche im Vergleich zu den allein durch die Radionuklide verursachten Schäden festgestellt.

Schlussfolgerung Wir schließen daraus, dass keine direkte Abhängigkeit besteht, was den Mechanismus der Strangbruchinduktion und das Fehlen oder Vorhandensein von an die DNA gebundenen Platinatomen anbelangt. Die berichteten zunehmenden DNA-Schäden bei Therapieansätzen auf zellulärer Ebene hängen stark vom Studiendesign ab und werden hauptsächlich durch die Reparaturmechanismen in lebenden Zellen beeinflusst. Dennoch ist die Verwendung von radioaktivem Cisplatin, das den Auger-Elektronenemitter ¹⁹¹Pt, ^193mPt oder ^195mPt enthält, eine glänzende Perspektive für zukünftige Therapien zum Abtöten von Tumorzellen, die 2 Wirkprinzipien kombiniert: ein Zytostatikum und ein Radiopharmakon gleichzeitig.

Schlüsselwörter

Cisplatin - Kombinationstherapie - radiosensibilisierende Effekte - Strahlentherapie - Auger-Therapie

Keywords

Cisplatin - Combination Therapy - Radiosensitizing Effects - Radiotherapy - Auger Therapy

Publication History

Received: 09 July 2021

Accepted after revision: 22 January 2022

Article published online:
06 April 2022

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