In vitro Comparative Study of the Antitumor Effects of Human Interferon‐α, β and γ on the Growth and Invasive Potential of Human Melanoma Cells

Horikoshi, Takashi; Fukuzawa, Kumiko; Hanada, Nirou; Ezoe, Kyori; Eguchi, Hiroaki; Hamaoka, Shuji; Tsujiya, Hidenobu; Tsukamoto, Taiji

doi:10.1111/j.1346-8138.1995.tb03889.x

Cited by 36 publications

(20 citation statements)

References 17 publications

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“…It seems to be an essential mediator not only for the host defense in the innate immune responses against microbial infections but also for a host defense system against oncogenesis (28). Few studies showed that IFN-h has greater antitumor effects than IFN-a via the activation of apoptosis (17)(18)(19)(20)(21). Therefore, IFN-h represents a promising drug in the treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

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IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

et al. 2006

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IFN-A controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-B, has not been evaluated. We compared the antitumor effects of IFN-A and IFN-B in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-B significantly inhibited BON cell growth in a time-and dose-dependent manner. IC 50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN-A resulted significantly in a less potent effect (IC 50 : 44 IU/mL, maximal inhibition: 26%). IFN-A induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-B, apart from a more potent delay in S-G 2 -M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-B severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-B is much more potent, compared with IFN-A, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-B has comparable potent tumor growth inhibitory effects in vivo. (Cancer Res 2006; 66(1): 554-62)

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Section: Discussionmentioning

confidence: 99%

“…For all these reasons, novel treatment strategies seem mandatory. Few authors reported that IFN-h has greater antitumor effects than IFN-a on melanoma, squamous carcinoma, glioma, breast, and hepatocellular cancer (17)(18)(19)(20)(21). On these bases, IFN-h seems to be of potential interest in the treatment of tumors.…”

Section: Introductionmentioning

confidence: 99%

IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

et al. 2006

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“…We chose to focus on hIFN-␤ because of its reported stronger antiproliferative activity against other tumor types. [11][12][13][14] The use of our immunodeficient model offers an opportunity to selectively assess the antiproliferative effects of hIFN-␤ in the absence of its immunomodulatory 15 and direct antiangiogenic properties, 16 because hIFN-␤ does not cross-react with its cognate murine receptor. 17 In our initial experiments, recombinant hIFN-␤ was administered either subcutaneously (2000 IU per mouse thrice weekly) or intravenously (60 000 IU per mouse daily) into cohorts of ␤2m null NOD/SCID mice a week after intravenous injection with HL-60 cells with an additional untreated cohort (n ϭ 10) serving as controls.…”

Section: Effects Of Ifn-␣ and ␤ On Aml Cell Lines In Vitro And In Vivomentioning

confidence: 99%

Continuous delivery of human type I interferons (α/β) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model

Benjamin

Khwaja

Singh

et al. 2006

Blood

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IntroductionDespite significant advances in the treatment of acute myeloid leukemia (AML), long-term survival is limited to about 30% of patients; hence the urgent need for alternative treatment strategies. 1 Type I IFNs (IFN-␣ and IFN-␤) have shown considerable promise in the treatment of many solid tumors 2 and have proven to be highly effective in several hematologic malignancies, including chronic myeloid leukemia. 3 Although in vitro studies with type I IFNs have shown impressive cytotoxicity against AML cells, 4 their antitumor efficacy in vivo remains largely untested in animal models or in patients with AML, except for the United Kingdom Medical Research Council (UK MRC) AML 11 trial, in which maintenance treatment with IFN-␣ failed to prevent relapse or improve overall survival. 5 However, it remains unclear whether this lack of efficacy was related to poor antileukemic effect in vivo or a failure to maintain stable therapeutic IFN-␣ levels because of its short half-life. 6 In this study, we compare the antileukemic effects of IFN-␣ and ␤ against a variety of AML cell lines in a xenograft model. Two different schedules of administration were used: the traditional high-dose multiple bolus injection approach using recombinant IFN-␤, as well as continuous low-dose delivery, achieved here through gene transfer with adenoassociated virus (AAV) vectors. Materials and methods Cell culture and cell proliferation assaysThe AML cell lines HL-60, KG1␣, AML193, and OCI AML5 were cultured in RPMI medium with 10% fetal calf serum. GM-CSF at 100 pg/mL was added to the medium for AML193 and OCI AML5 cells. Frozen AML cells obtained from leukopheresis of patients with poor-risk AML were used for our primary AML experiments. Cell lines were seeded in 96-well plates at 20 000 cells per well to which varying concentrations of recombinant human IFN␤-1a or IFN␣-2b were added. Following stimulation for 3 or 5 days, cells were pulsed with 3 H-thymidine (0.5 Ci [0.0185 MBq] per well) for 4 hours, harvested, and 3 H-thymidine incorporation measured by scintillation counting. AAV2/8 hIFN-␤ and AAV2/8 hFIX vector productionAs previously described, recombinant AAV vectors pseudotyped with serotype 8 capsid were generated by transient transfection of 293T cells using either the pAV2 CAGG hIFN-␤ or pAV2 CAGG human factor IX (hFIX) control vector plasmids together with pAAV2/8 packaging and pHTGI adeno helper plasmids. 7 The AAV2/8 vectors were purified using an ion exchange chromatography method, and slot blot analysis was used to determine the titer of the vectors. Human IFN␣-2b and IFN␤-1a bioassayPlasma levels of human IFN-␣ and IFN-␤ were determined using a validated antiviral assay with a sensitivity of 0.5 IU/mL as described before. 8

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“…Notwithstanding IFN-␤ half-life (1 h) is shorter than that of IFN-␣ (4 -7 h), several studies showed that IFN-␤ has more potent antitumor effects than IFN-␣, via the activation of apoptosis (6,8,12,16,27,(31)(32)(33). In addition, new strategies could improve in future the pharmacokinetic and pharmacodynamic profile of IFN-␤, like the pegylated formulation (21).…”

Section: Discussionmentioning

confidence: 99%

Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

Vitale

Koetsveld

Herder

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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We recently demonstrated that interferon (IFN)-β has a more potent antitumor activity than IFN-α in BON cells, a neuroendocrine tumor (NET) cell line. The present study showed the role of type I IFNs in the modulation of the insulin-like growth factor (IGF) system in NETs. BON cells expressed IGF-I, IGF-II, IGF-I receptor, and insulin receptor mRNA. In addition, IGF-I and IGF-II stimulated the proliferation of BON cells and induced an inhibition of DNA fragmentation (apoptosis). As evaluated by quantitative RT-PCR, treatment with IFN-α (100 IU/ml) or IFN-β (100 IU/ml) inhibited the expression of IGF-II mRNA (−42% and −65%, respectively, both P < 0.001), whereas IGF-I receptor mRNA was significantly upregulated by IFN-α (+28%, P < 0.001) and downregulated by IFN-β (−47%, P < 0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-α (−16%, P < 0.05) and IFN-β (−69%, P < 0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (−54%) after IFN-β treatment. Scatchard analysis of 125I-labeled IGF-I binding to cell membrane of BON cells revealed a dramatic suppression of maximum binding capacity only in the presence of IFN-β. Finally, the proapoptotic activity of IFN-β was partially counteracted by the coadministration of IGF-I and IGF-II (both at 50 nM). In conclusion, these data demonstrate that the IGF system has an important role in autocrine/paracrine growth of BON cells. The more potent antitumor activity of IFN-β compared with IFN-α could be explained by several effects on this system: 1) both IFNs inhibit the transcription of IGF-II, but the suppression is significantly higher after IFN-β than IFN-α and 2) only IFN-β inhibits the expression of IGF-I receptor.

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In vitro Comparative Study of the Antitumor Effects of Human Interferon‐α, β and γ on the Growth and Invasive Potential of Human Melanoma Cells

Cited by 36 publications

References 17 publications

IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

IFN-β Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

Continuous delivery of human type I interferons (α/β) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model

Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

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