Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors

Christine Dufès, W. Nicol Keith, Alan Bilsland, Irina Proutski, Ijeoma F. Uchegbu, Andreas G. Schätzlein

Research output: Contribution to journalArticle

  • 109 Citations

Abstract

The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.
LanguageEnglish
Pages8079-84
Number of pages7995
JournalCancer Research
Volume65
Issue number18
DOIs
StatePublished - 2005

Fingerprint

Synthetic Genes
Dendrimers
Medicine
Genetic Therapy
Tumor Necrosis Factor-alpha
Neoplasms
Transgenes
Transfection
Plasmids
Genes
Therapeutics
Telomerase
Heterografts
Cervix Uteri
Nanoparticles
Squamous Cell Carcinoma
Colorectal Neoplasms
Adenocarcinoma
Neoplasm Metastasis
Injections

Keywords

  • cancer
  • cancer research
  • biomedical sciences
  • pharmacology
  • anticancer gene medicine
  • antitumor activity
  • cationic vector
  • tumors

Cite this

Dufès, C., Keith, W. N., Bilsland, A., Proutski, I., Uchegbu, I. F., & Schätzlein, A. G. (2005). Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors. Cancer Research, 65(18), 8079-84. DOI: 10.1158/0008-5472.CAN-04-4402
Dufès, Christine ; Keith, W. Nicol ; Bilsland, Alan ; Proutski, Irina ; Uchegbu, Ijeoma F. ; Schätzlein, Andreas G./ Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors. In: Cancer Research. 2005 ; Vol. 65, No. 18. pp. 8079-84
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abstract = "The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100{\%} of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.",
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Dufès, C, Keith, WN, Bilsland, A, Proutski, I, Uchegbu, IF & Schätzlein, AG 2005, 'Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors' Cancer Research, vol. 65, no. 18, pp. 8079-84. DOI: 10.1158/0008-5472.CAN-04-4402

Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors. / Dufès, Christine; Keith, W. Nicol; Bilsland, Alan; Proutski, Irina; Uchegbu, Ijeoma F.; Schätzlein, Andreas G.

In: Cancer Research, Vol. 65, No. 18, 2005, p. 8079-84.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors

AU - Dufès,Christine

AU - Keith,W. Nicol

AU - Bilsland,Alan

AU - Proutski,Irina

AU - Uchegbu,Ijeoma F.

AU - Schätzlein,Andreas G.

PY - 2005

Y1 - 2005

N2 - The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.

AB - The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.

KW - cancer

KW - cancer research

KW - biomedical sciences

KW - pharmacology

KW - anticancer gene medicine

KW - antitumor activity

KW - cationic vector

KW - tumors

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UR - http://dx.doi.org/10.1158/0008-5472.CAN-04-4402

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DO - 10.1158/0008-5472.CAN-04-4402

M3 - Article

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EP - 8084

JO - Cancer Research

T2 - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -