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Therapeutic properties of a vector carrying the HSV thymidine kinase and GM-CSF genes and delivered as a complex with a cationic copolymer.

Alekseenko IV, Snezhkov EV, Chernov IP, Pleshkan VV, Potapov VK, Sass AV, Monastyrskaya GS, Kopantzev EP, Vinogradova TV, Khramtsov YV, Ulasov AV, Rosenkranz AA, Sobolev AS, Bezborodova OA, Plyutinskaya AD, Nemtsova ER, Yakubovskaya RI, Sverdlov ED - J Transl Med (2015)

Bottom Line: We tried to overcome these constraints through a combination of suicide gene therapy with immunomodulating therapy.The system HSVtk-GM-CSF/PEI-PEG was tested in vitro in various mouse and human cell lines, ex vivo and in vivo using mouse models.Our data indicate that combined suicide and cytokine gene therapy may provide a powerful approach for the treatment of solid tumors and their metastases.

View Article: PubMed Central - PubMed

Affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. irina.alekseenko@mail.ru.

ABSTRACT

Background: Gene-directed enzyme prodrug therapy (GDEPT) represents a technology to improve drug selectivity for cancer cells. It consists of delivery into tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. Major limitations of GDEPT that hinder its clinical application include inefficient delivery into cancer cells and poor prodrug activation by suicide enzymes. We tried to overcome these constraints through a combination of suicide gene therapy with immunomodulating therapy. Viral vectors dominate in present-day GDEPT clinical trials due to efficient transfection and production of therapeutic genes. However, safety concerns associated with severe immune and inflammatory responses as well as high cost of the production of therapeutic viruses can limit therapeutic use of virus-based therapeutics. We tried to overcome this problem by using a simple nonviral delivery system.

Methods: We studied the antitumor efficacy of a PEI (polyethylenimine)-PEG (polyethylene glycol) copolymer carrying the HSVtk gene combined in one vector with granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA. The system HSVtk-GM-CSF/PEI-PEG was tested in vitro in various mouse and human cell lines, ex vivo and in vivo using mouse models.

Results: We showed that the HSVtk-GM-CSF/PEI-PEG system effectively inhibited the growth of transplanted human and mouse tumors, suppressed metastasis and increased animal lifespan.

Conclusions: We demonstrated that appreciable tumor shrinkage and metastasis inhibition could be achieved with a simple and low toxic chemical carrier - a PEI-PEG copolymer. Our data indicate that combined suicide and cytokine gene therapy may provide a powerful approach for the treatment of solid tumors and their metastases.

No MeSH data available.


Related in: MedlinePlus

Survival of S37-bearing mice after injection of TK-PPT, mGM-PPT and TKmGM-PPT with or without ganciclovir. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct), TK (CMV-HSVtk-pGL3), mGM (CMVmGM-CSF-pGL3); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.
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Fig3: Survival of S37-bearing mice after injection of TK-PPT, mGM-PPT and TKmGM-PPT with or without ganciclovir. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct), TK (CMV-HSVtk-pGL3), mGM (CMVmGM-CSF-pGL3); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.

Mentions: As seen from Table 1 and Figure 3, intratumoral injections of the TK/GCV or TKmGM/GCV polyplexes had a biologically significant antitumor effect. On day 30, the extension of animal lifespan in mice treated with TKmGM/GCV and TK/GCV was as high as 70 and 62%, respectively. The tumor growth delay (TGD500) for the combination TKmGM/GCV was 14.1 days, and for the combination TK/GCV – 11.6 days.Figure 3


Therapeutic properties of a vector carrying the HSV thymidine kinase and GM-CSF genes and delivered as a complex with a cationic copolymer.

Alekseenko IV, Snezhkov EV, Chernov IP, Pleshkan VV, Potapov VK, Sass AV, Monastyrskaya GS, Kopantzev EP, Vinogradova TV, Khramtsov YV, Ulasov AV, Rosenkranz AA, Sobolev AS, Bezborodova OA, Plyutinskaya AD, Nemtsova ER, Yakubovskaya RI, Sverdlov ED - J Transl Med (2015)

Survival of S37-bearing mice after injection of TK-PPT, mGM-PPT and TKmGM-PPT with or without ganciclovir. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct), TK (CMV-HSVtk-pGL3), mGM (CMVmGM-CSF-pGL3); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359447&req=5

Fig3: Survival of S37-bearing mice after injection of TK-PPT, mGM-PPT and TKmGM-PPT with or without ganciclovir. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct), TK (CMV-HSVtk-pGL3), mGM (CMVmGM-CSF-pGL3); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.
Mentions: As seen from Table 1 and Figure 3, intratumoral injections of the TK/GCV or TKmGM/GCV polyplexes had a biologically significant antitumor effect. On day 30, the extension of animal lifespan in mice treated with TKmGM/GCV and TK/GCV was as high as 70 and 62%, respectively. The tumor growth delay (TGD500) for the combination TKmGM/GCV was 14.1 days, and for the combination TK/GCV – 11.6 days.Figure 3

Bottom Line: We tried to overcome these constraints through a combination of suicide gene therapy with immunomodulating therapy.The system HSVtk-GM-CSF/PEI-PEG was tested in vitro in various mouse and human cell lines, ex vivo and in vivo using mouse models.Our data indicate that combined suicide and cytokine gene therapy may provide a powerful approach for the treatment of solid tumors and their metastases.

View Article: PubMed Central - PubMed

Affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997, Russia. irina.alekseenko@mail.ru.

ABSTRACT

Background: Gene-directed enzyme prodrug therapy (GDEPT) represents a technology to improve drug selectivity for cancer cells. It consists of delivery into tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. Major limitations of GDEPT that hinder its clinical application include inefficient delivery into cancer cells and poor prodrug activation by suicide enzymes. We tried to overcome these constraints through a combination of suicide gene therapy with immunomodulating therapy. Viral vectors dominate in present-day GDEPT clinical trials due to efficient transfection and production of therapeutic genes. However, safety concerns associated with severe immune and inflammatory responses as well as high cost of the production of therapeutic viruses can limit therapeutic use of virus-based therapeutics. We tried to overcome this problem by using a simple nonviral delivery system.

Methods: We studied the antitumor efficacy of a PEI (polyethylenimine)-PEG (polyethylene glycol) copolymer carrying the HSVtk gene combined in one vector with granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA. The system HSVtk-GM-CSF/PEI-PEG was tested in vitro in various mouse and human cell lines, ex vivo and in vivo using mouse models.

Results: We showed that the HSVtk-GM-CSF/PEI-PEG system effectively inhibited the growth of transplanted human and mouse tumors, suppressed metastasis and increased animal lifespan.

Conclusions: We demonstrated that appreciable tumor shrinkage and metastasis inhibition could be achieved with a simple and low toxic chemical carrier - a PEI-PEG copolymer. Our data indicate that combined suicide and cytokine gene therapy may provide a powerful approach for the treatment of solid tumors and their metastases.

No MeSH data available.


Related in: MedlinePlus