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Doxycycline Inducible Melanogenic Vaccinia Virus as Theranostic Anti-Cancer Agent.

Kirscher L, Deán-Ben XL, Scadeng M, Zaremba A, Zhang Q, Kober C, Fehm TF, Razansky D, Ntziachristos V, Stritzker J, Szalay AA - Theranostics (2015)

Bottom Line: In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models.Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography.At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.

View Article: PubMed Central - PubMed

Affiliation: 1. University of Würzburg, Department of Biochemistry, Am Hubland, 97074 Würzburg, Germany.

ABSTRACT
We reported earlier the diagnostic potential of a melanogenic vaccinia virus based system in magnetic resonance (MRI) and optoacoustic deep tissue imaging (MSOT). Since melanin overproduction lead to attenuated virus replication, we constructed a novel recombinant vaccinia virus strain (rVACV), GLV-1h462, which expressed the key enzyme of melanogenesis (tyrosinase) under the control of an inducible promoter-system. In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models. Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography. At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.

No MeSH data available.


Related in: MedlinePlus

Ex vivo vMSOT-images and photographs of GLV-1h462 infected A549 tumor xenografts with or without doxycycline induction. At each time point the same two excised A549 tumors of identical treatment are shown as 3D-reconstruction vMSOT images (upper 2 panels; pink represents tumor tissue; black represents melanin in tumor tissue), vMSOT maximum intensity projection images (middle 2 panels) and photographic pictures (lower 2 panels). Melanin specific signal intensity in the vMSOT images is presented as heat map. Left and right columns show the non-induced group (-), middle columns show tumors of doxycycline treated mice (+). Each column represents one time point after induction with doxycycline. The orientation of the tumors is not identical between the images.
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Figure 6: Ex vivo vMSOT-images and photographs of GLV-1h462 infected A549 tumor xenografts with or without doxycycline induction. At each time point the same two excised A549 tumors of identical treatment are shown as 3D-reconstruction vMSOT images (upper 2 panels; pink represents tumor tissue; black represents melanin in tumor tissue), vMSOT maximum intensity projection images (middle 2 panels) and photographic pictures (lower 2 panels). Melanin specific signal intensity in the vMSOT images is presented as heat map. Left and right columns show the non-induced group (-), middle columns show tumors of doxycycline treated mice (+). Each column represents one time point after induction with doxycycline. The orientation of the tumors is not identical between the images.

Mentions: We reported earlier that rVACV dependent melanin production in infected tumor cells was visualized with magnetic resonance imaging (MRI) and multispectral optoacoustic tomography (MSOT) 7. Here, we investigated if the dox inducible melanogenic reporter system GLV-1h462 is also suitable for both imaging technologies. Moreover, we wanted to know how early melanin could be detected by either technology after dox induction in mice. We therefore excised A549 tumor xenografts at different times after the induction with dox and analyzed the MRI and volumetric MSOT (vMSOT) signals from these samples. Already 4 days post induction (dpi) clear melanin dependent vMSOT-signals were detected which were confirmed by visual inspections revealing the production of melanin (Fig. 6). Moreover, the melanin specific signals in vMSOT increased over time. The last time point measured (18dpi) showed the highest signal intensity while the non-induced GLV-1h462 infected A549 xenografts showed no or very little melanin specific signal. In PANC-1 tumors, we detected a melanin signal in GLV-1h460 and in induced GLV-1h462 colonized xenografts while no or very little melanin-dependent vMSOT-signal was observed in GLV-1h312 and uninduced GLV-1h462 tumors (Supplementary Fig. S3A).


Doxycycline Inducible Melanogenic Vaccinia Virus as Theranostic Anti-Cancer Agent.

Kirscher L, Deán-Ben XL, Scadeng M, Zaremba A, Zhang Q, Kober C, Fehm TF, Razansky D, Ntziachristos V, Stritzker J, Szalay AA - Theranostics (2015)

Ex vivo vMSOT-images and photographs of GLV-1h462 infected A549 tumor xenografts with or without doxycycline induction. At each time point the same two excised A549 tumors of identical treatment are shown as 3D-reconstruction vMSOT images (upper 2 panels; pink represents tumor tissue; black represents melanin in tumor tissue), vMSOT maximum intensity projection images (middle 2 panels) and photographic pictures (lower 2 panels). Melanin specific signal intensity in the vMSOT images is presented as heat map. Left and right columns show the non-induced group (-), middle columns show tumors of doxycycline treated mice (+). Each column represents one time point after induction with doxycycline. The orientation of the tumors is not identical between the images.
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Related In: Results  -  Collection

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Figure 6: Ex vivo vMSOT-images and photographs of GLV-1h462 infected A549 tumor xenografts with or without doxycycline induction. At each time point the same two excised A549 tumors of identical treatment are shown as 3D-reconstruction vMSOT images (upper 2 panels; pink represents tumor tissue; black represents melanin in tumor tissue), vMSOT maximum intensity projection images (middle 2 panels) and photographic pictures (lower 2 panels). Melanin specific signal intensity in the vMSOT images is presented as heat map. Left and right columns show the non-induced group (-), middle columns show tumors of doxycycline treated mice (+). Each column represents one time point after induction with doxycycline. The orientation of the tumors is not identical between the images.
Mentions: We reported earlier that rVACV dependent melanin production in infected tumor cells was visualized with magnetic resonance imaging (MRI) and multispectral optoacoustic tomography (MSOT) 7. Here, we investigated if the dox inducible melanogenic reporter system GLV-1h462 is also suitable for both imaging technologies. Moreover, we wanted to know how early melanin could be detected by either technology after dox induction in mice. We therefore excised A549 tumor xenografts at different times after the induction with dox and analyzed the MRI and volumetric MSOT (vMSOT) signals from these samples. Already 4 days post induction (dpi) clear melanin dependent vMSOT-signals were detected which were confirmed by visual inspections revealing the production of melanin (Fig. 6). Moreover, the melanin specific signals in vMSOT increased over time. The last time point measured (18dpi) showed the highest signal intensity while the non-induced GLV-1h462 infected A549 xenografts showed no or very little melanin specific signal. In PANC-1 tumors, we detected a melanin signal in GLV-1h460 and in induced GLV-1h462 colonized xenografts while no or very little melanin-dependent vMSOT-signal was observed in GLV-1h312 and uninduced GLV-1h462 tumors (Supplementary Fig. S3A).

Bottom Line: In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models.Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography.At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.

View Article: PubMed Central - PubMed

Affiliation: 1. University of Würzburg, Department of Biochemistry, Am Hubland, 97074 Würzburg, Germany.

ABSTRACT
We reported earlier the diagnostic potential of a melanogenic vaccinia virus based system in magnetic resonance (MRI) and optoacoustic deep tissue imaging (MSOT). Since melanin overproduction lead to attenuated virus replication, we constructed a novel recombinant vaccinia virus strain (rVACV), GLV-1h462, which expressed the key enzyme of melanogenesis (tyrosinase) under the control of an inducible promoter-system. In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models. Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography. At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.

No MeSH data available.


Related in: MedlinePlus