Anti-tumor activity of cytokines against opportunistic vascular tumors in mice

Dong, Qiang; Graziani, Andrea; Garlanda, Cecilia; Calmanovici, R. Wainstock De; Arese, Marco; Soldi, Rafaella; Vecchi, Annunciata; Mantovani, Alberto; Bussolino, Federico

doi:10.1002/(sici)1097-0215(19960301)65:5<700::aid-ijc23>3.0.co;2-9

Cited by 11 publications

(9 citation statements)

References 25 publications

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“…17 In particular, anti -H5V hemangiosarcoma responses were found to be potentiated by IFN and IL -12, while they were abrogated by anti -T-cell antibodies. 17,19,39 Our analysis of H5V lesions expression profiles indicated that inhibition of disease development in infected mice was associated with the persistent infiltration of stagnating tumors with activated effectors (CTL and NK ) cells. Thus, we hypothesize that the parvovirus -mediated toxicity of NS1 for H5V cells stimulated intrinsic immune reaction, and that this response was intensified when the virus expressed IP -10 transgene in addition to its own NS1 and NS2 genes.…”

Section: Discussionmentioning

confidence: 86%

“…(c ) Although no total cure was achieved, responding to therapy mice stayed alive for more than 6 months, which represents an over 100 days increase in their life expectancy ( the equivalent of 10 years of human lifespan ). The antitumor protection provided by MVMp / IP -10 is quite impressive because H5V model is an especially aggressive case of experimental hemangiosarcomas, which are usually refractory to complete cure by various treatments, 16,39,44,45 with IL-12 therapy being the most successful one. 19 The antineoplastic activity of IP -10 is not without precedents, although the use of different delivery systems and tumor models precludes published data from being quantitatively compared with the present ones.…”

Section: Discussionmentioning

confidence: 99%

“…Especially conspicuous was the high production of IFN transcripts in virus -treated tumor remnants, as compared to mock -treated growing lesions ( Fig 4B ). Accumulation of IFN can thus be assumed to contribute to suppression of tumor progression, this cytokine being both directly cytotoxic to H5V cells 39 and capable of stimulating the granzyme /perforinmediated cytotoxic activity of effector immune cells. 40 Suppression of distant metastases is associated with reduction of PAI -1 expression in livers.…”

Section: Potential Mechanism Of Mvmp and Mvmp / Ip -10 Action Againstmentioning

confidence: 99%

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Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

et al. 2002

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We have previously shown that the growth of human tumor xenografts in immunodeficient mice can be efficiently suppressed upon infection with the autonomous parvovirus H -1 or with cytokine -transducing derivatives thereof. To further evaluate the benefits of implementing parvoviruses in cancer gene therapy, we have created a new recombinant vector, MVMp / IP -10, transducing the immunoactive, antiangiogenic chemokine IP -10, and used this virus to treat syngeneic tumors grown in immunocompetent mice. Intratumoral / intraperitoneal administration of only 3Â10 7 replication units of MVMp / IP -10 per animal strongly inhibited the progression of established H5V cell -induced vascular tumors, a highly malignant mouse model for human cavernous hemangioma and Kaposi's sarcoma. Retardation of recurrent tumor growth and suppression of life -threatening metastatic dissemination to internal organs were accompanied by a striking delay in hemangioma -associated mortality. Parental MVMp did not have a significant effect under these conditions up to the dose of 10 10 infectious units / animal, but had strong antihemangiosarcoma activity when used to infect H5V cells ex vivo prior to implantation. In all cases, virus therapy was very well tolerated. Virus -induced suppression of hemangiosarcoma was dependent on host T cells and associated with intratumoral persistence of IFN -expressing cytotoxic lymphocytes, and led to the reduced expression of hepatic plasminogen activator inhibitor -1 ( PAI -1 ), a metastasis -linked marker. This proof of principle study demonstrates that MVMp / IP -10 can aid the treatment of vascular tumors and that autonomous parvovirus -based vectors can be considered potent tools for cancer gene therapy purposes.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Potential Mechanism Of Mvmp and Mvmp / Ip -10 Action Againstmentioning

confidence: 99%

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Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

et al. 2002

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“…These changes suggest a possible relationship between the dierent levels of PymT and of pp60 c-src activity and the dierences in the proliferative response of EC. In contrast, murine EC lines carrying mT and established by embryonic tissues have an increased and permanent activation of signaling pathways triggered by mT, including phosphatidylinositol 3-kinase (Dong et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Human endothelial cells expressing polyoma middle T induce tumors

et al. 2000

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“…Altematively, IL-12 may inhibit tumour cell proliferation by triggering IFN-y production by T lymphocytes and NK cells Nastala et al, 1994). Our previous studies indicated that IFN-y suppresses H5V cell proliferation in vitro as well as tumour growth in vivo (Dong et al, 1996). In line with these findings, we observed that anti-IFN-y MAb co-administration abrogated the anti-tumour effect conferred by IL-12 treatment, thus IFN-y production is essential for anti-tumour activity of IL-12.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity

Vízler

Rosato²,

Calderazzo³

et al. 1998

Br J Cancer

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Summary In syngeneic mice, the H5V polyoma middle-T oncogene-transformed endothelioma cell line induces Kaposi's sarcoma-like cavernous haemangiomas that regress transiently, probably because of an anti-tumour immune response, but eventually grow progressively and kill the host. To evaluate the generation of tumour-specific cytotoxic T lymphocytes (CTLs), spleen cells of tumour-bearing mice were restimulated with irradiated H5V cells in mixed leucocyte-tumour cell cultures. Tumour-specific CTLs were demonstrable only when low numbers of H5V stimulator cells were used (<1 H5V cell per 50 splenocytes). We found that H5V cells secrete immunosuppressive mediators because CTL generation was blocked when H5V cells culture supernatants were added to allogeneic mixed leucocyte cultures. As numerous tumour-derived immunosuppressive mediators may interfere with interleukin 12 (IL-12) production, we tested whether IL-12 treatment of the tumour-bearing mice would augment their immune response and thus suppress tumour growth. Indeed, IL-12 inhibited tumour growth and prevented mortality, but did not increase anti-H5V CTL generation either in vitro or in vivo. Moreover, the anti-tumour activity in IL-12-treated mice was abrogated by anti-interferon (IFN)-y monoclonal antibody (MAb) co-administration. These results strongly suggest that the antitumour effect of IL-12 is principally mediated by IFN-y release that in turn blocks H5V cell proliferation and induces the release of factors that suppress angiogenesis.

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Anti-tumor activity of cytokines against opportunistic vascular tumors in mice

Abstract: o 1996 Wiley-Liss, Inc.

Cited by 11 publications

References 25 publications

Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

Suppression of metastatic hemangiosarcoma by a parvovirus MVMp vector transducing the IP-10 chemokine into immunocompetent mice

Human endothelial cells expressing polyoma middle T induce tumors

Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity

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