Abstract:
Localizing the cytotoxic effects of cancer therapies to only affect the tumor cells is a goal in oncology, to maximize efficacy and minimize treatment-related morbidities. Most effective chemotherapeutic drugs have significant side effects due to off-target toxicity. By comparison, photodynamic therapy (PDT) is a localized therapy without significant systemic toxicity but may have limited efficacy. Hence, combining PDT with chemotherapy was investigated to determine if the anti-tumor effect of the latter could be enhanced. PDT using indocyanine green (ICG), activated by near-infrared light, was investigated in lung tumor cells in vitro in combination with cisplatin or etoposide (VP-16). The combination of cisplatin and ICG-PDT had significant concentration-dependent dark toxicity, with little additional cell kill after light exposure. Conversely, combination therapy comprising 5 μm VP-16, 50 μm ICG and 50 J/cm2 808-nm radiant exposure resulted in ~10% clonogenic cell survival compared to ~80% cell survival with either treatment alone. This potentially synergistic gain was achieved only when both treatments were given at the same time or when VP-16 was administered 4 h prior to PDT. VP-16 given 4 h post PDT did not show any added benefit over PDT alone.
Zusammenfassung:
Ein Ziel der Onkologie besteht darin, die zytotoxische Wirkung von Krebstherapien genau auf die Tumorzellen zu fokussieren, um so die Wirksamkeit der Behandlung zu maximieren und gleichzeitig die behandlungsbedingte Morbidität zu verringern. Gerade die wirksamsten Chemotherapeutika haben jedoch erhebliche Nebenwirkungen durch ihre Off-Target-Toxizität. Im Vergleich dazu ist die photodynamische Therapie (PDT) eine lokalisierte Therapie ohne signifikante systemische Toxizität, die jedoch eine begrenzte Wirksamkeit haben kann. Die vorliegende Studie untersucht daher inwiefern die Anti-Tumor-Wirkung einer Chemotherapie durch eine Kombination aus PDT und Chemotherapie verbessert werden kann. Durchgeführt wurden In-Vitro-Versuche an Lungentumorzellen, die mittels Indocyaningrün (ICG)-vermittelter PDT in Kombination mit Cisplatin oder Etoposid (VP-16) behandelt wurden. Das ICG wurde durch Licht im nahen Infrarot aktiviert. Die Kombination aus Cisplatin und ICG-PDT zeigte eine signifikante konzentrationsabhängige Dunkeltoxizität, mit geringer zusätzlicher Zellabtötung nach der Belichtung. Umgekehrt führte eine Kombinationstherapie aus 5 μm VP-16, 50 μm ICG und 50 J/cm2 Laserbestrahlung mit 808 nm zu ~10% klonogenem Zellüberleben im Vergleich zu ~80% bei alleiniger PDT-Behandlung. Diese potentiell synergistische Verstärkung wurde nur erreicht, wenn beide Behandlungen gleichzeitig erfolgten oder wenn VP-16 ca. 4 Stunden vor der PDT verabreicht wurde. VP-16 gegeben 4 h nach der PDT hatte hingegen keinen zusätzlichen Vorteil gegenüber einer alleinigen PDT-Behandlung.
Acknowledgments
This work was supported by an Innovation grant from the Canadian Cancer Society Research Institute (Grant number: ‘2012-701479’). Additional funding was provided by the Ontario Ministry of Health and Long Term Care. The authors would like to thank Dr. Qing-Bin Lu at University of Waterloo for stimulating these studies.
Conflict of interest statement: Authors state no conflict of interest. All authors have read the journal’s Publication Ethics and Publication Malpractice Statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.
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