Liposome-mediated gene transfer into human basal cell carcinoma

Hottiger, Michael O.; Dam, Tomas Norman; Nickoloff, Brian J.; Johnson, Timothy M.; Nabel, Gary J.

doi:10.1038/sj.gt.3301036

Cited by 20 publications

(13 citation statements)

References 31 publications

(41 reference statements)

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“…Thus, our data indicate that IFNa does reduce cell viability in ASZ001 cells. These data are consistent with IFN-based therapy of human BCCs that administration of IFNs results in tumor shrinkage (Grob et al, 1988;Chimenti et al, 1995;Hottiger et al, 1999). There are at least two possibilities through which cell viability is reduced: inhibition of cell proliferation (DNA synthesis) or promotion of apoptosis.…”

Section: Ifna-mediated Apoptosis In Bccssupporting

confidence: 74%

“…Amounting evidence supports that exogenous interferon (IFN)a or stimulating IFNa secretion is an effective way for BCC therapy, either intralesionally or topically (Grob et al, 1988;Chimenti et al, 1995;Hottiger et al, 1999). Intratumoral injection of recombinant interferons has been shown to result in complete remission in 47-86% of patients with BCC (Grob et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling

Chi

et al. 2003

Oncogene

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Basal cell carcinoma (BCC), the most common form of human cancer, is understood to be associated with activation of the sonic hedgehog pathway, through lossof-function mutations of tumor suppressor PTCH1 or gain-of-function mutations of smoothened. Interferon (IFN)-based therapy is quite effective in BCC treatment, but the molecular basis is not well understood. Here we report a novel mechanism by which IFNa mediates apoptosis in BCCs. In the presence of IFNa, we observed increased apoptosis in a BCC cell line ASZ001, in which PTC is null, and therefore with constitutive activation of the sonic hedgehog pathway. We demonstrate that SMO agonist Ag-1.4 mediates activation of extracellular signalregulated kinase (Erk) phosphorylation, which is abrogated by IFNa in sonic hedgehog responsive C3H10T1/2 cells. In transient transfection experiments, we demonstrate that IFNa inhibits Erk phosphorylation and serum response element activation induced by expression of SMO, Gli1, PDGFRa and activated Raf, but not activated mitogen-activated Erk-regulating kinase (Mek), suggesting that IFNa targets mainly on Mek function. We further show that IFNa induces expression of Fas in BCC cells through interfering with Mek function. The role of the Fas-L/Fas signaling axis in IFNa-mediated apoptosis is demonstrated by the fact that addition of Fas-L neutralizing antibodies, just as caspase-8 inhibitor Z-IETD-FMK, effectively prevents IFNa-mediated apoptosis. Thus, our data indicate that IFNa-based BCC therapy induces Fas expression and apoptosis through interfering with Mek function.

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Section: Ifna-mediated Apoptosis In Bccssupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling

Chi

et al. 2003

Oncogene

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“…By contrast, improved therapeutic effect and safety are expected for IFN-a gene transfer, because it allows an increased and sustained local concentration of this cytokine in the target sites while minimising unnecessary systemic distribution (Suzuki et al, 2003;Hatanaka et al, 2004). In fact, it has been reported that direct IFN-a gene transfer into tumours suppressed growth of various cancers such as breast cancer, prostate cancer, renal cancer, hepatocellular carcinoma, basal cell carcinoma and leukaemia (Zhang et al, 1996;Coleman et al, 1998;Hottiger et al, 1999;Iqbal Ahmed et al, 2001). Although no study of IFN-a gene transfer against pancreatic cancer had been reported, we recently found that the expression of IFN-a effectively induced growth suppression and cell death in pancreatic cancer cells, an effect that appeared to be more prominent than in other types of cancers and normal cells (Hatanaka et al, 2004).…”

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confidence: 99%

Adenovirus-mediated interferon α gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer

Ohashi¹,

Yoshida²,

Kushida³

et al. 2005

Br J Cancer

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We previously demonstrated a characteristically high sensitivity of pancreatic cancer cells to interferon alpha (IFN-a) gene transfer, which induced a more prominent growth suppression and cell death in pancreatic cancer cells than in other types of cancers and normal cells. The IFN-a protein can exhibit both direct cytotoxicity and indirect immunological antitumour activity. Here, we dissected and examined the two mechanisms, taking advantage of the fact that IFN-a did not show any cross-species activity in its in vivo effect. When a human IFN-a adenovirus was injected into subcutaneous xenografts of human pancreatic cancer cells in nude mice, tumour growth was significantly suppressed due to cell death in an adenoviral dose-dependent manner. The IFN-a protein concentration was markedly increased in the injected subcutaneous tumour, but leakage of the potent cytokine into the systemic blood circulation was minimal. When a mouse IFN-a adenovirus was injected into the same subcutaneous tumour system, all mice showed significant tumour inhibition, an effect that was dependent on the indirect antitumour activities of IFN-a, notably a stimulation of natural killer cells. Moreover, in this case, tumour regression was observed not only for the injected subcutaneous tumours but also for the untreated tumours at distant sites. This study suggested that a local IFN-a gene therapy is a promising therapeutic strategy for pancreatic cancer, due to its dual mechanisms of antitumour activities and lack of significant toxicity.

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“…3 Although ex vivo IFN-␣ gene therapy has demonstrated tumor inhibition and elicited tumor-specific immune memory, [4][5][6][7][8] this approach is patient-specific and time-consuming. Direct intratumoral injection of IFN-␣ DNA to treat solid Renca, 9 basal cell carcinoma, 10 and hetero-xenograft prostatic (PC-3) or hepatocellular carcinoma (Hep3B) 11 with the use of viral or liposome-based nonviral delivery systems has effectively suppressed tumors in in vivo mouse models. Intratumoral delivery of the IFN-␣ gene using a simple, powerful approach -electroporation -to treat tumors, however, has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Regression of tumors by IFN-α electroporation gene therapy and analysis of the responsible genes by cDNA array

Xia

Zhang

et al. 2002

Gene Ther

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Liposome-mediated gene transfer into human basal cell carcinoma

Cited by 20 publications

References 31 publications

IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling

IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling

Adenovirus-mediated interferon α gene transfer induces regional direct cytotoxicity and possible systemic immunity against pancreatic cancer

Regression of tumors by IFN-α electroporation gene therapy and analysis of the responsible genes by cDNA array

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