Reduction of Liver Metastasis of Intraocular Melanoma by Interferon-β Gene Transfer

Alizadeh, Hassan; Howard, Kevin; Mellon, J. Killian; Mayhew, Elizabeth; Rusciano, Dario; Niederkorn, Jérry Y.

doi:10.1167/iovs.02-1147

Cited by 28 publications

(32 citation statements)

References 48 publications

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“…The liver enzyme aspartate transaminase (AST) was significantly lower (P < 0.05, Mann-Whitney U test) in melittin-loaded nanoparticle-treated mice (329 ± 162 U/l) than in saline-treated controls bearing tumors (2097 ± 1162 U/l). Because elevated levels of AST commonly accompany liver metastases, the lower levels in the treated mice are consistent with inhibition of liver metastases (32,33), although this remains to be proved.…”

Section: Melittin-loaded Nanoparticle Synthesis and Action On Cancer mentioning

confidence: 96%

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Soman¹,

Baldwin²,

Hu³

et al. 2009

J. Clin. Invest.

265

277

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The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

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Section: Melittin-loaded Nanoparticle Synthesis and Action On Cancer mentioning

confidence: 96%

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Soman¹,

Baldwin²,

Hu³

et al. 2009

J. Clin. Invest.

265

277

View full text Add to dashboard Cite

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“…9 This hypothesis is supported by numerous studies using gene therapy approaches in both murine and human solid tumor models. [10][11][12][13][14][15][16][17] Moreover, we and others have shown that intralesional delivery of the IFN-b gene, which allows for the accumulation of higher intratumoral concentrations of IFN-b, is able to suppress primary tumors, prolong the survival of tumor-bearing mice, and protect against a second challenge in syngeneic mice. 12,18,19 Nitric oxide (NO) is a small molecule produced by mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

et al. 2006

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We have previously reported that adenoviral vector-mediated interferon (IFN)-b gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immunecompetent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-b therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-b1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-b gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-b antitumoral effects in vivo.

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“…[35][36][37][38][39][40][41][42][43][44][45][46][47] The mechanism of action is complex as type I interferons induce a pleiotropic array of responses, including direct inhibition of growth of various tumors cells and modulation of host immune cells such as natural killer (NK) cells, 35,39,41,43,44,46 polymorphonuclear (PMN) cells, 43 macrophages, 36,39,41,47 CD4( þ ) 41,43 and CD8( þ ) 36,[41][42][43] cells. In most studies, as we observed in the experiments reported herein, local adenovirus mediated IFNb gene therapy was preferred over systemic due to increased local transgene concentrations and reduced toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…36,37,40,41,47 On the other hand, systemic delivery of Ad-IFNb resulted in efficient hepatocyte transduction with the vector and potent liver metastases inhibition. 35,46 An interesting distinction between the two type I IFNs is the relative essential role for the effect of IFNb on stimulation of immune cells as there was a loss of efficacy in tumor bearing SCID-BEIGE. 42 In contrast, we observed significant efficacy with tumor IFNa treatment in immunocomprimised mice, suggesting the induction of responses not dependent on T-lymphocyte function, were sufficient to elicit tumor growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus delivery provides extended interferon-α exposure and augments treatment of metastatic carcinoma

Brin¹,

Atencio²,

Helmich³

et al. 2006

Cancer Gene Ther

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Type I interferons (e.g. IFNa2b) have been successfully used to treat a variety of hematological malignancies, but have not been efficacious for treatment of most solid tumors. We tested the hypothesis that delivery of type I interferon utilizing recombinant adenovirus (rAd) vectors may improve treatment efficacy of metastatic carcinomas by providing increased interferon exposure resulting from continuous transgene expression. Treatment of mice with a rAd-vector expressing hybrid-IFN (rAd-IFNa2a1) inhibited 4T1 mammary carcinoma tumor growth and induced tumor regression in a dose-dependent manner. Moreover, rAd-IFNa2a1 treatment reduced hepatic and pulmonary metastatic burden. A comparison of local and systemic routes of administration demonstrated that intratumoral delivery of rAd-IFNa2a1 was sufficient for inhibition of tumor growth. Moreover, it reduced toxicity associated with high-dose systemic IFNa2a1 exposure. Interestingly, antitumor activity following intratumoral treatment was due, in part, to the immunostimulatory capacity of the rAd vector component. Furthermore, systemic administration of rAd-IFNa2a1 potentiated the immunotherapeutic effect induced by local intralesional delivery of empty-rAd vector. These results suggest continuous interferon-a exposure may provide improved antitumor responses for metastatic carcinomas. Additionally, immunostimulatory responses induced by rAd-IFNa2a1 may mitigate the immune-evasive tumor microenvironment.

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Reduction of Liver Metastasis of Intraocular Melanoma by Interferon-β Gene Transfer

Abstract: The results support the feasibility of activation of NK cell function through gene transfer as one possible therapeutic strategy for reducing hepatic metastases of uveal melanomas.

Cited by 28 publications

References 48 publications

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth

Inducible nitric oxide synthase activity is essential for inhibition of prostatic tumor growth by interferon-β gene therapy

Adenovirus delivery provides extended interferon-α exposure and augments treatment of metastatic carcinoma

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