Aplidin as a potential adjunct to radiation therapy: In vitro studies

Abstract

Purpose: Aplidin (plitidespin) is a novel cyclic depsipeptide, currently in Phase II clinical trials for solid and hematologic malignancies. We examined the effects of oxygen on the cytotoxicity of Aplidin and the interactions between Aplidin and radiation. These factors will be important if Aplidin is used clinically in combination with radiotherapy.

Materials: Exponentially-growing EMT6 mouse mammary tumour cells in monolayer cultures were treated with Aplidin and 250 kV X-rays.

Results: The cytotoxicity of Aplidin was not altered either by incubation in moderate hypoxia before and during a 24 h drug treatment or by incubation in severe hypoxia before and during a 2 h drug treatment. Treatment with Aplidin plus radiation produced cytotoxicities compatible with additive or supraadditive cytotoxicities. Cells treated with 1 μM Aplidin for 24 h then killed by 100 Gy of radiation were toxic to untreated cells co-cultured with them.

Conclusions: The cytotoxicity of Aplidin is independent of the oxygenation during treatment. Aplidin, or an active metabolite of Aplidin, is retained in the cells and later released as the radiation-sterilised cells die, producing a Bystander effect that kills neighbouring cells. This Bystander effect could affect the outcome of therapeutic regimens combining Aplidin and radiation.

Keywords:

• Aplidin
• radiation
• oxygenation
• Bystander effects

Acknowledgements

The authors thank Jacqueline Mendes for her assistance with the experiments reported here and Bettina Harris for her assistance with the preparation of the manuscript. We also thank PharmaMar for their support of this research and for providing the Aplidin for these studies. We thank Dr Enrique Alvarez for his discussions of these experiments and the results.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.