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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

Histological images of tumors and lymph nodes. Subcutaneously transplanted mouse sarcoma 37 on day 15 of tumor growth (a,d). Metastatic ipsilateral inguinal lymph nodes on the day 30 of tumor growth in control mice (b,c,f,g). Images show tumor cells infiltrating lymph node parenchyma (f) and totally replacing lymph node tissue (g). A lymph node taken on day 30 after the beginning of the treatment from a mouse treated with TKmGM/GCV (h); note that its parenchyma is free of tumor cells. The sections are made through the largest cross dimension of the tissue samples. Low-power field images (a-d, 40×) demonstrate differences in size between positive (metastatic) and negative (metastasis free) lymph nodes. High-power field images (e-h, 400×) represent detailed histological features of the specimens. Formalin fixed and paraffin embedded tissues (H&E staining).
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Fig4: Histological images of tumors and lymph nodes. Subcutaneously transplanted mouse sarcoma 37 on day 15 of tumor growth (a,d). Metastatic ipsilateral inguinal lymph nodes on the day 30 of tumor growth in control mice (b,c,f,g). Images show tumor cells infiltrating lymph node parenchyma (f) and totally replacing lymph node tissue (g). A lymph node taken on day 30 after the beginning of the treatment from a mouse treated with TKmGM/GCV (h); note that its parenchyma is free of tumor cells. The sections are made through the largest cross dimension of the tissue samples. Low-power field images (a-d, 40×) demonstrate differences in size between positive (metastatic) and negative (metastasis free) lymph nodes. High-power field images (e-h, 400×) represent detailed histological features of the specimens. Formalin fixed and paraffin embedded tissues (H&E staining).

Mentions: The bilateral inguinal lymph nodes of each mouse bearing sarcoma 37 were histologically examined to reveal metastatic involvement at the end of the surveillance period. Histological structure of the primary tumor and typical histological findings in the tissues of dissected lymph nodes are represented in Figure 4 (see a-c, e-g).Figure 4


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)

Histological images of tumors and lymph nodes. Subcutaneously transplanted mouse sarcoma 37 on day 15 of tumor growth (a,d). Metastatic ipsilateral inguinal lymph nodes on the day 30 of tumor growth in control mice (b,c,f,g). Images show tumor cells infiltrating lymph node parenchyma (f) and totally replacing lymph node tissue (g). A lymph node taken on day 30 after the beginning of the treatment from a mouse treated with TKmGM/GCV (h); note that its parenchyma is free of tumor cells. The sections are made through the largest cross dimension of the tissue samples. Low-power field images (a-d, 40×) demonstrate differences in size between positive (metastatic) and negative (metastasis free) lymph nodes. High-power field images (e-h, 400×) represent detailed histological features of the specimens. Formalin fixed and paraffin embedded tissues (H&E staining).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Histological images of tumors and lymph nodes. Subcutaneously transplanted mouse sarcoma 37 on day 15 of tumor growth (a,d). Metastatic ipsilateral inguinal lymph nodes on the day 30 of tumor growth in control mice (b,c,f,g). Images show tumor cells infiltrating lymph node parenchyma (f) and totally replacing lymph node tissue (g). A lymph node taken on day 30 after the beginning of the treatment from a mouse treated with TKmGM/GCV (h); note that its parenchyma is free of tumor cells. The sections are made through the largest cross dimension of the tissue samples. Low-power field images (a-d, 40×) demonstrate differences in size between positive (metastatic) and negative (metastasis free) lymph nodes. High-power field images (e-h, 400×) represent detailed histological features of the specimens. Formalin fixed and paraffin embedded tissues (H&E staining).
Mentions: The bilateral inguinal lymph nodes of each mouse bearing sarcoma 37 were histologically examined to reveal metastatic involvement at the end of the surveillance period. Histological structure of the primary tumor and typical histological findings in the tissues of dissected lymph nodes are represented in Figure 4 (see a-c, e-g).Figure 4

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