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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 period of mice inoculated with A) adenocarcinoma C26; B) cervical squamous carcinoma CSC5 after injection of TKmGM-PPT. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.
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Fig5: Survival period of mice inoculated with A) adenocarcinoma C26; B) cervical squamous carcinoma CSC5 after injection of TKmGM-PPT. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.

Mentions: The data obtained showed (Table 2, Figure 5) that treatment with TKmGM-PPT plus GCV had a biologically significant antitumor effect in animals with C26 tumors. On day 26 in the case of C26 ILS was 42%. TGD1500 in the animals with С26 was 8.5 days. In the case of CSC5 we observed TGD1000 equal to 6 days and a modest or even biologically insignificant extension of animal lifespan (23%). It may be due to the specific properties of CSC5 tumor or to a non-optimal scheme of treatment for this type of cancer. Injection of constructs without GCV or solely GCV did not appreciably affect tumor growth.Table 2


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 period of mice inoculated with A) adenocarcinoma C26; B) cervical squamous carcinoma CSC5 after injection of TKmGM-PPT. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct); 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

Fig5: Survival period of mice inoculated with A) adenocarcinoma C26; B) cervical squamous carcinoma CSC5 after injection of TKmGM-PPT. TKmGM (CMV-HSVtk-mGM-CSF-pGL3 construct); PPT - polyethylenimine-polyethylene glycol-TAT peptide copolymer; PBS – phosphate buffered saline (placebo); GCV – ganciclovir.
Mentions: The data obtained showed (Table 2, Figure 5) that treatment with TKmGM-PPT plus GCV had a biologically significant antitumor effect in animals with C26 tumors. On day 26 in the case of C26 ILS was 42%. TGD1500 in the animals with С26 was 8.5 days. In the case of CSC5 we observed TGD1000 equal to 6 days and a modest or even biologically insignificant extension of animal lifespan (23%). It may be due to the specific properties of CSC5 tumor or to a non-optimal scheme of treatment for this type of cancer. Injection of constructs without GCV or solely GCV did not appreciably affect tumor growth.Table 2

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