Interferons (IFNs) have established antitumor action; the mechanism underlying this effect is, however, not yet clear. To probe the possible contribution of inhibition of angiogenesis, we have assessed angiogenesis in the mouse initiated by either human or murine tumor cell lines. Whether test cells were inoculated in the dermis or tumor fragments were grafted onto the cornea, tumor-induced angiogenesis (TIA) was inhibited by IFNs. TIA was also inhibited by the potent IFN inducer polyriboinosinic-polyribocytidylic acid. The effect of IFN was species specific; human IFNs inhibited human tumors and mouse IFNs inhibited murine tumors. This effect suggested that in contrast to other angiogenesis inhibitors, IFNs modulated the signal for angiogenesis produced by the tumor cells. Tumor cells treated in vitro with homologous IFN were significantly (P less than 0.005) less competent to initiate angiogenesis than were untreated cells. Inhibition of angiogenesis was achieved whether vascular response was assessed 1 or 3 days after tumor cell inoculation, suggesting that antiangiogenesis activity was independent of the antiproliferative effects of IFNs. To further substantiate this, L1210 leukemia cells, resistant to the antiproliferative effects of IFNs, were treated with 500 units/ml IFN-beta. IFN had no effect on their proliferation, but in four separate experiments, L1210R cells were impaired in their ability to induce angiogenesis. Thus, inhibition of TIA by IFNs was species specific, occurred at least partly by modulation of the signal inducing angiogenesis, and was expressed in the absence of antiproliferative effects. IFNs also inhibited immunologically induced angiogenesis, whether initiated by allogeneic lymphocytes (LIA) or by the mouse's own T-cells in response to an exogenous antigen (sheep RBC). LIA was markedly suppressed by treatment of host mice with homologous IFN-beta. For example, mean vessel counts induced by allogeneic mouse lymphocytes were decreased from 22.8 +/- 1.4 (SE) to 12.5 +/- 0.8 (P less than 0.0001); mouse IFN-beta had no corresponding effect on xenogeneic human lymphocytes (mean vessel counts decreased to 21.7 +/- 2.6 from 22.7 +/- 2.0). Treatment with human IFN-alpha, -beta, or -gamma in vitro or host mice in vivo reduced the ability of inoculated human peripheral blood lymphocytes to initiate xenogeneic LIA. Inhibition of LIA required a lower dose and/or a shorter incubation period than that needed to modulate TIA. Treatment of the donor of the allogeneic spleen cells in vivo with murine IFN or inducers also resulted in lesser LIA.(ABSTRACT TRUNCATED AT 400 WORDS)

https://cancerres.aacrjournals.org/content/canres/47/19/5155.full.pdf

Inhibition of Angiogenesis by Interferons: Effects on Tumor-and Lymphocyte-induced Vascular Responses

Anticancer research on the plant species Rhodiola rosea L. (Crassulaceae) has begun in animal models in 1987. In combination with cyclophosphamide, R. rosea extract enhanced the anti-tumor and anti-metastatic effects of drug treatment and reduced drug-induced toxicity. Combined with Adriamycin ® , it improved inhibition of tumor dissemination and prevented liver toxicity. The aim of the present work was to study the effect of rosavin and aqueous and 50% hydroalcoholic extracts of R. rosea roots and rhizomes on neovascular reaction induced in the skin of Balb/c mice after grafting of L-1 sarcoma cells. Mice were treated per os with 50, 100, 200 and 400 µg of extracts, or were fed rosavin in daily doses 2, 4 and 8 µg. After 72 hours mice were sacrificed with lethal dose of Morbital. All newly formed blood vessels were identified and counted in dissection microscope. Both extracts in 100-400 µg daily doses and rosavin in the highest dose highly significantly decreased neovascular reaction.

https://www.termedia.pl/Journal/-10/pdf-10364-1?filename=The influence of Rhodiola.pdf

Experimental immunology The influence of Rhodiola rosea extracts and rosavin on cutaneous angiogenesis induced in mice after grafting of syngeneic tumor cells

/pdf/the-influence-of-rhodiola-rosea-extracts-and-rosavin-on-2qiamyxlo5.pdf

The influence of Rhodiola rosea extracts and rosavin on cutaneous angiogenesis induced in mice after grafting of syngeneic tumor cells

Background: We have previously shown, using the chicken embryo chorioallantoic membrane (CAM) model of in vivo angiogenesis, that X-rays act on the extracellular matrix and enhance normal and tumor-induced angiogenesis. In the present work, we studied the effect of X-rays on the gene expression of three proteins that are important regulators of angiogenesis: vascular endothelial growth factor (VEGF), heparin affin regulatory peptide (HARP) and inducible nitric oxide synthase (iNOS). Materials and Methods: An area of 1 cm 2 of the CAM, restricted by a plastic ring, was irradiated at room temperature. The expression of the genes was studied using RT-PCR and the amounts of the mRNAs were quantified using image analysis of the corresponding agarose gels of the RT-PCR products. Results: VEGF mRNA was decreased 6 h after irradiation. However, at later time points, VEGF expression was significantly increased compared with the non- irradiated tissue. Similarly, X-rays down-regulated both HARP and iNOS expression 6 h after irradiation and the effect was reversed at later time points, similarly to the effect of X-rays on VEGF. Conclusion: These data support the notion that X-rays increase the expression of genes that favor angiogenesis. Radiation therapy is considered to inhibit angiogenesis through damage to the endothelium (1-3). However, there are also in vivo studies that show that X-rays induce angiogenesis (4, 5). Since the exact mechanisms of action of ionizing radiation on tissues remain unclear, it has not been easy to explain this discrepancy. We have recently shown, in the in vivo chicken embryo chorioallantoic membrane (CAM) model of angiogenesis, that X-rays influence the expression, deposition and turnover of extracellular matrix (ECM) proteins in a way that secondarily favors both normal and tumor-induced angiogenesis (6).

X-rays affect the expression of genes involved in angiogenesis.

Angiogenesis and cardioprotection after TNFα-inducer-Tolpa Peat Preparation treatment in rat's hearts after experimental myocardial infarction in vivo

X-irradiation enhanced a new blood vessel formation occurring in the course of a local GvH reaction in mice. Maximal enhancing effect was exerted by single total body irradiation doses ranging from 700 to 1050 R. Fractionation in daily doses smaller than 200 R did not exhibit enhancing effect. Proliferative ability of angiogenesis inducing cells is not necessary for enhancing effect of irradiation.

Enhancing effect of X-ray irradiation on a new blood vessel formation in mice tested by lymphocyte induced angiogenesis assay.

Angiogenesis induction by xenogeneic lymphoid and non-lymphoid cells in mice.

Three assays estimating the local graft-versus-host (GVH) reaction were compared in normal and immunosuppressed mice. The GVH reaction was evoked by administration of spleen cells from normal or specifically immunized donors: a) under the kidney capsule by the Elkins technique, b) subcutaneously in the foot pad, for the popliteal lymph node weight gain (PLN) assay, and c) intradermally, for lymphocyte-induced angiogenesis (LIA) assay. In the Elkins model, the intensity of the GVH reaction was estimated by the weight ratio of the injected to the non-injected kidney and by the microscopic evaluation of infiltrative and destructive changes in renal parenchyma. In PLN assay, the draining to the contralateral popliteal lymph node weight ratio was measured, and in the LIA assay, the number of newly formed blood vessels directed the injection site was counted. The sensitivity of Elkins local GVH model was shown to be the lowest as compared with PLN or LIA assay, the latter being the most sensitive and rapid.

Bem W

Papers

Enhancing effect of X-ray irradiation on a new blood vessel formation in mice tested by lymphocyte induced angiogenesis assay.

Angiogenesis induction by xenogeneic lymphoid and non-lymphoid cells in mice.

Comparison of three assays measuring the local graft-versus-host (GVH) reaction in mice.