Intratumor injection of small interfering RNA-targeting human papillomavirus 18 E6 and E7 successfully inhibits the growth of cervical cancer

Fujii, Takuma; Saito, Masafumi; E, Iwasaki; Ochiya, Takahiro; Takei, Yoshiyuki; Hayashi, Shigenori; Ono, Akiko; Hirao, Nobumaru; Nakamura, Masaru; Kubushiro, Kaneyuki; Tsukazaki, Katsumi; Aoki, Daisuke

doi:10.3892/ijo.29.3.541

Cited by 45 publications

(44 citation statements)

References 24 publications

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“…Previous studies, including our own, have demonstrated that silencing HPV E6/E7, with siRNA or short hairpin RNA (shRNA), leads to cervical cancer cells undergoing apoptosis or senescence [11][12][13][14] and inhibition of tumor growth in vivo. [14][15][16][17] These results suggest that RNAi therapy could be developed for cervical cancer treatment. However, for this treatment to become a reality a number of issues need to be addressed including achieving stable and durable RNAi.…”

Section: Introductionmentioning

confidence: 93%

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Payne

Sun

et al. 2010

Cancer Gene Ther

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RNA interference (RNAi)-based gene silencing is widely used in laboratories for gene function studies and also holds a great promise for developing treatments for diseases. However, in vivo delivery of RNAi therapy remains a key issue. Lentiviral vectors have been employed for stable gene transfer and gene therapy and therefore are expected to deliver a stable and durable RNAi therapy. But this does not seem to be true in some disease models. Here, we showed that lentivirus delivered short-hairpin RNA (shRNA) against human papillomavirus (HPV) E6/E7 oncogenes were effective for only 2 weeks in a cervical cancer model. However, using this vector to carry two copies of the same shRNA or two shRNAs targeting at two different but closely related genes (HPV E6 and vascular endothelial growth factor) was more effective at silencing the gene targets and inhibiting cell or even tumor growth than their single shRNA counterparts. The cancer cells treated with dual shRNA were also more sensitive to chemotherapeutic drugs than single shRNA-treated cells. These results suggest that a multi-shRNA strategy may be a more attractive approach for developing an RNAi therapy for this cancer.

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Section: Introductionmentioning

confidence: 93%

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Payne

Sun

et al. 2010

Cancer Gene Ther

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“…Although these particles have not been modified to target tumors, passive targeting due to the enhanced permeability and retention effect, causes the selective accumulation within the cancerous tissues as shown in several studies with tumor xenografts. 23,[37][38][39] Initial studies indicated that atelocollagen particles could be administered safely without induction of cytokines or observed toxicity to the tissues.…”

Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

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Harnessing RNA interference using small RNA-based drugs has great potential to develop drugs designed to knock down expression of any disease-causing gene, thereby greatly expanding the universe of possible drug targets. However, delivering small RNAs into specific tissues and cells is still a hurdle. Here, we review recent progress in overcoming systemic, local and cellular barriers to RNA drug delivery, focusing on strategies for targeted uptake.

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“…Atelocollagen, which is prepared from bovine dermis, 17,18 contributes to increases in cellular uptake, nuclease resistance and the prolonged release of siRNA, 14,[19][20][21] as well as plasmid DNA, 17 and antisense oligonucleotide compounds, 10,11,13,22 administered to tumors. An siRNAatelocollagen complex also can be delivered via an intravenous injection route as nanoparticles, enabling systemic delivery of siRNAs.…”

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confidence: 99%

Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl‐xL and cisplatin against prostate cancer

Nagahara

Makita

et al. 2009

Intl Journal of Cancer

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The largest obstacle to the effective use of short interfering RNA (siRNA) in an animal body is the ability to deliver it to the target tissue. Here we showed a systemic delivery method of siRNA specific to pregrown solid tumors via atelocollagen. Atelocollagen facilitated the selective uptake of siRNA into the tumors when an siRNA/atelocollagen complex was administered intravenously to mice. We chose a Bcl‐xL protein as a model target to prove the therapeutic efficacy of the atelocollagen‐mediated method. Bcl‐xL acts as an anti‐apoptotic factor, which is overexpressed in many cancers, including prostate cancer. One of the four designed siRNAs to human Bcl‐xL potently inhibited the expression of Bcl‐xL by the PC‐3 human prostate cancer cell line in vitro, leading to cell apoptosis. Intravenous injections for3 consecutive days (siRNA, 100 μg/injection per day as a complex with atelocollagen) effectively downregulated Bcl‐xL expression in the PC‐3 xenograft. We administered four series of 3 consecutive days of intravenous injections each, for a total of 12 injections, which significantly inhibited tumor growth when the treatment was combined with cisplatin (2 mg/kg). Local injection of Bcl‐xL siRNA also potently inhibited tumor growth. All of the tumors treated with Bcl‐xL siRNA/atelocollagen complex via both intravenous and intratumoral injection showed terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling‐positive apoptosis. There were no severe side effects such as interferon‐α induction and liver or renal damage in mice. Our results indicate that systemic delivery of siRNA via atelocollagen, which specifically targets tumors, is safe and feasible for cancer therapy. © 2009 UICC

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Intratumor injection of small interfering RNA-targeting human papillomavirus 18 E6 and E7 successfully inhibits the growth of cervical cancer

Cited by 45 publications

References 24 publications

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Inhibition of cervical cancer cell growth in vitro and in vivo with dual shRNAs

Special delivery: targeted therapy with small RNAs

Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl‐xL and cisplatin against prostate cancer

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