Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI– p53 complexes

Densmore, Charles L.; Kleinerman, Eugenie S.; Gautam, Ajay Kumar; Jia, Shu Fang; Xu, Bo; Worth, Laura L.; Waldrep, J. Clifford; Fung, Y. K.; Tang, Anne; Knight, Vernon

doi:10.1038/sj.cgt.7700343

Cited by 66 publications

(45 citation statements)

References 19 publications

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“…We have previously reported that aerosol delivery of chemical agents and genes was an effective method for targeting these agents to the pulmonary region. 3,[16][17][18] This method of delivery significantly altered the agent's biodistribution and pharmacokinetics in favor of pulmonary deposition, which included the peripheral areas of the lung, an area where OS metastases are frequently found. 19,20 GCB is a nucleoside analogue, which has a different mechanism of anticancer activity than standard drugs used for OS treatment.…”

Section: Discussionmentioning

confidence: 99%

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

Koshkina

Kleinerman

2005

Intl Journal of Cancer

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Osteosacarcoma (OS) lung metastases are often resistant to chemotherapy. Most anticancer drugs are administered systemically. In many cases this is followed by dose-dependent toxicity, which may not allow the achievement of therapeutic levels in lungs to eradicate metastases. We determined the efficacy of gemcitabine (GCB) by administering it directly to the lungs via aerosol and studied the role of the Fas pathway in response to the therapy. We used 2 osteosarcoma lung metastases animal models: human LM7 cells that form lung metastases in mice following intravenous injection and murine LM8 cells, which grows subcutaneously in mice and spontaneously metastasize to the lung. Treatment was initiated when the presence of lung metastases had been established. Aerosol GCB inhibited the growth of lung metastases in mice. Intraperitoneal GCB administration at similar dosage had no effect on lung metastases. Besides its direct effect on lung metastases, aerosol GCB suppressed the growth of subcutaneous LM8 tumor. Histopathological examination of mice receiving aerosol GCB showed no evidence of toxicity. Lungs are distinguished from other tissues by the constitutive expression of FasL. Since exposure of tumor cells to GCB upregulated Fas expression, we hypothesized that the susceptibility of the tumor cells to ligandinduced cell death by resident lung cells may be increased. Therefore, the Fas pathway may contribute to the therapeutic effect of aerosol GCB. ' 2005 Wiley-Liss, Inc. Key words: Fas; lung environment; toxicityThe most common site for metastatic spread of OS is the lungs. Patients with OS lung metastases have a poor prognosis with limited therapeutic options. Metastatic and relapsed disease is often resistant to salvage chemotherapy. Our laboratory's goal is to identify new therapeutic approaches for these patients.GCB has been shown to have limited efficacy in the treatment of advanced sarcomas, including OS, 1 but this may be explained in part because systemic administration of GCB does not achieve therapeutic levels in the lungs. We hypothesized that targeted delivery of GCB to the lungs via aerosol will circumvent this problem, yielding a higher drug concentration in the area of the tumor and offer a unique therapeutic opportunity for patients with lung metastases. Indeed, we previously demonstrated that the intranasal administration of GCB at a dose 8-fold lower than the i.v. dose induced the regression of established OS lung metastases. 2 However, the intranasal delivery of drugs to the lungs in humans is not ideal as the drugs will not reach the peripheral regions of the lungs where metastases often develop.Aerosol delivery can bypass this limitation. The clinical feasibility of aerosol drug delivery has been demonstrated with both 9-nitrocamptothecin and GM-CSF. 3,4 In our study, we investigated the efficacy of aerosol GCB in treating OS lung metastases using 2 OS animal model. Aerosol GCB significantly inhibited the growth of primary tumors and of established lung metastases and also prevented metast...

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Section: Discussionmentioning

confidence: 99%

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

Koshkina

Kleinerman

2005

Intl Journal of Cancer

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“…Preclinical data are available for hepatocellular carcinoma, 1 pancreatic tumors, 2,3 ovarian carcinoma, 4,5 head-andneck cancer 6,7 and lung cancer. [8][9][10] More importantly, the first clinical data were published recently, which show dramatic bladder tumor remission in two patients. 11 Despite recent advances in chemotherapy, ovarian cancer remains the leading cause of death by gynecological malignancy in Western countries.…”

Section: Introductionmentioning

confidence: 99%

Intraperitoneal linear polyethylenimine (L-PEI)-mediated gene delivery to ovarian carcinoma nodes in mice

Dutoit

Denoux

et al. 2005

Cancer Gene Ther

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Linear polyethylenimine (L-PEI) is an efficient transfection agent for ovarian carcinoma cells in vitro and ex vivo. In the present work, we go a step further and evaluate the efficacy of L-PEI in human ovarian tumor nodes developed in mice. PEI/DNA complexes were administered intraperitoneally instead of intravenously to avoid sequestering of complexes in the lung and liver and to allow transfection of nonvascularized tumor nodes. Plasmid biodistribution was studied by PCR and gene expression was characterized using complementary luciferase and b-galactosidase assays. Intraperitoneal (i.p.) injection of L-PEI/DNA complexes allowed the straightforward distribution of plasmid in the whole peritoneal cavity. Gene expression occurred in many organs, but tumor nodes appeared as preferential sites for transgene expression. The i.p. delivery route allowed repeated injections and administration of large amounts of DNA (up to 400 mg) without signs of toxicity, even for doses well beyond the intravenous lethal dose. Transgene expression was dose-dependent and transient. However, multiple injections allowed its persistence to increase. These results provide encouraging elements towards the development of PEI-based gene therapy protocols for the treatment of advanced stage ovarian carcinoma.

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“…4,6 We have previously demonstrated that polyethylenimine (PEI) can achieve high levels of transgene expression in the lungs after aerosol delivery, 6 with minimal toxicity or cytokine responses, 6,7 and the dose delivered by aerosol has been shown to result in an anti-tumor effect in two different lung cancer models, using the p53 tumor suppressor gene. 8,9 Also, we previously reported that aerosol delivery of a liposomal formulation of 9NC, a topoisomerase I inhibitor, can inhibit the growth of subcutaneous tumors as well as lung metastases. 10,11 In this report, we demonstrate that sequential delivery of p53 and 9NC by aerosol can arrest the growth of established B16-F10 melanoma pulmonary metastases in experimental mice.…”

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confidence: 99%

Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin

et al. 2002

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Growth inhibition of established tumor metastases in the lungs poses a difficult challenge for most clinical settings inLung cancer is the single largest cause of cancer deaths, with less than 15% of newly diagnosed patients surviving beyond 5 years. More than 80% of lung cancers do not respond favorably to chemotherapy. One of the primary clinical challenges is to overcome the tumor resistance to chemotherapeutic drugs. P53 tumor suppressor gene mutations are reported in a majority of lung cancers and loss of p53 function results in increased drug resistance and tumor relapse. 1 An approach postulated in recent years is p53 gene replacement into the tumor cells, which can then lead the cell into apoptosis as well as increase the sensitivity of the cells to chemotherapeutic drugs. 2,3 Most anti-cancer drugs have been conventionally delivered via oral or intravenous routes. Biodistribution of the drugs through these delivery strategies is widespread, with the ratio of the drug deposited in the lungs being low. 4 A similar distribution of transgene expression in various tissues is observed after intravenous or intraperi- toneal delivery of vector-DNA complexes for gene therapy. 5 Another concern is the systemic toxicity observed after oral or intravenous routes of delivery. Aerosol delivery of genes and chemotherapeutic drugs represents a very promising technology to target the lungs specifically, increasing the pulmonary deposition and pharmacokinetic profile of the drugs and genes. 4,6 We have previously demonstrated that polyethylenimine (PEI) can achieve high levels of transgene expression in the lungs after aerosol delivery, 6 with minimal toxicity or cytokine responses, 6,7 and the dose delivered by aerosol has been shown to result in an anti-tumor effect in two different lung cancer models, using the p53 tumor suppressor gene. 8,9 Also, we previously reported that aerosol delivery of a liposomal formulation of 9NC, a topoisomerase I inhibitor, can inhibit the growth of subcutaneous tumors as well as lung metastases. 10,11 In this report, we demonstrate that sequential delivery of p53 and 9NC by aerosol can arrest the growth of established B16-F10 melanoma pulmonary metastases in experimental mice.In order to study the combined effect of 9NC and p53 in vitro, B16-F10 cells grown in tissue culture plates were transfected with PEI-p53 or PEI-Neobam complexes (1

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Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI– p53 complexes

Cited by 66 publications

References 19 publications

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

Aerosol gemcitabine inhibits the growth of primary osteosarcoma and osteosarcoma lung metastases

Intraperitoneal linear polyethylenimine (L-PEI)-mediated gene delivery to ovarian carcinoma nodes in mice

Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin

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