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T Tsutsui

Publications and source records attributed to T Tsutsui.

At least 109 records · Page 6Linked to original sources
PubMed1997

Enhanced induction of very late antigen 4/lymphocyte function-associated antigen 1-dependent T-cell migration to tumor sites following administration of interleukin 12.

Administration of interleukin 12 (IL-12) into mice bearing CSA1M, OV-HM, Meth A, or MCH-1-A1 tumor induced complete regression of CSA1M and OV-HM tumors but induced only a slight growth inhibition of Meth A and MCH-1-A1 tumors. These effects of IL-12 were associated with high and only marginal levels of T-cell infiltration into CSA1M/OV-HM and Meth A/MCH-1-A1 tumor masses, respectively. Here, we investigated the role of IL-12 in the induction of T-cell migration. Spleen cells from untreated or IL-12-treated CSA1M-bearing mice were stained in vitro with a fluorescein chemical and transferred i.v. into IL-12-untreated CSA1M-bearing mice. Migration of donor cells was quantitated by counting the number of fluorescent cells on cryostat sections of tumor masses. Although only a slight migration was detected for spleen cells from IL-12-untreated CSA1M-bearing as well as IL-12-treated or untreated normal mice, enhanced migration was observed for cells from IL-12-treated CSA1M-bearing mice. A similar enhanced migration was observed for the OV-HM model. In contrast, such an enhancement was only marginal in the Meth A and MCH-1-A1 models. Immunohistochemical studies of tumors from IL-12-treated mice revealed that the predominant T-cell subset was CD4+ in CSA1M and CD8+ in OV-HM tumor masses. Consistent with this observation, the dominant subset of migrating T cells was found to be CD4+ in the CSA1M and CD8+ in the OV-HM models. T-cell migration was inhibited by pretreatment of recipients with either combination of anti-very late antigen 4 + anti-vascular cell adhesion molecule 1 or anti-lymphocyte function-associated antigen 1 + anti-intercellular adhesion molecule 1 monoclonal antibody. These results indicate that IL-12 can confer T cells with a capacity to migrate to tumor sites through very late antigen 4/lymphocyte function-associated antigen 1 adhesion pathways and that the in vivo acquisition of such a capacity following IL-12 treatment correlates with the induction of tumor regression.

Animals↗
PubMed1997

17beta-estradiol, diethylstilbestrol, tamoxifen, toremifene and ICI 164,384 induce morphological transformation and aneuploidy in cultured Syrian hamster embryo cells.

To examine the ability of estrogens and anti-estrogens to induce cellular transformation and genetic effects, Syrian hamster embryo (SHE) cells were treated with estrogens, 17beta-estradiol (E2) or diethylstilbestrol (DES), or with anti-estrogens, tamoxifen (TAM), toremifene (TOR) or ICI 164,384. Treatment with each substance for 1-3 days suppressed cellular growth in a dose-dependent manner. Colony-forming efficiency (CFE) increased following treatment of cells with E2 or DES for 48 hr at 3 or 10 microM but decreased at 20 or 30 microM. In contrast, CFE was increased by treatment with TAM, TOR or ICI 164,348 over the concentration range examined (1-30 microM). Treatment with each chemical at 1-30 microM for 48 hr caused morphological transformation of SHE cells in a dose-related fashion. The highest frequency was exhibited in SHE cells treated with DES at 20 microM and was 2 times higher than that induced by treatment with benzo[alpha]pyrene (B[alpha]P) at 4 microM. Transformation frequencies induced by other substances (E2, TAM, TOR and ICI 164,348) did not exceed that induced by the B[alpha]P treatment. TOR showed a higher transforming ability over all concentrations examined when compared to the other anti-estrogens (TAM and ICI 164,348). No significant increases in the frequencies of chromosomal aberrations were observed in SHE cells that were treated with any of the chemicals. However, treatment of SHE cells with each chemical induced a dose-dependent increase of aneuploid cells in the near diploid range. Our results indicate that the ability of the estrogens and anti-estrogens to induce numerical chromosomal abnormality may be involved in their cell transformation activity and potential carcinogenicity.

Aneuploidy↗
PubMed1997

Benzene-, catechol-, hydroquinone- and phenol-induced cell transformation, gene mutations, chromosome aberrations, aneuploidy, sister chromatid exchanges and unscheduled DNA synthesis in Syrian hamster embryo cells.

Benzene is a human carcinogen present naturally in petroleum and gasoline. For the simultaneous assessment of benzene-induced carcinogenicity and mutagenicity, benzene and its principal metabolites, phenol, catechol and hydroquinone were examined for their ability to induce cell transformation and genotoxic effects using the same mammalian cells in culture. Each of the four compounds induced morphological transformation of Syrian hamster embryo (SHE) cells. Catechol was the most potent, inducing transformation at concentrations of 1-30 microM, followed by hydroquinone (3-30 microM), phenol (10-100 microM) and benzene (only at 100 microM). Gene mutations at two loci in SHE cells were induced by all four compounds, with catechol being the most potent; both ouabain-resistant and 6-thioguanine-resistant mutant frequencies were increased. Chromosomal aberrations in SHE cells were especially induced by catechol, lesser by hydroquinone, and to a marginal extent by phenol at only the 100 microM concentration, whereas sister chromatid exchanges in SHE cells occurred with hydroquinone (1-30 microM), catechol (10-30 microM) and phenol (1000-3000 microM). Aneuploidy in the near diploid range of SHE cells was significantly induced by benzene and catechol. All three metabolites induced unscheduled DNA synthesis in SHE cells, whereas benzene did not. This is the first report that the cell transforming activity and mutagenicity of benzene and its metabolites were assessed with the same mammalian cells in culture. The results provide evidence that benzene and several of its metabolites are cell transforming and genotoxic to cultured mammalian cells.

Aneuploidy↗
PubMed1997

Extended lifespan and immortalization of human fibroblasts induced by X-ray irradiation.

The induction of immortalization of human fibroblasts by carcinogens is a very rare process. Hybrids between immortal cells and normal fibroblasts senesce, indicating that immortal cells must lose one or more senescence genes for immortalization. To examine the possible involvement of multiple gene alterations in extended lifespan or immortalization of normal human fibroblasts, normal human fibroblasts (WHE-7 cells) and skin fibroblasts (MDAH 087 cells) derived from a Li-Fraumeni syndrome patient with a mutated p53 allele were periodically irradiated with x rays. All six unirradiated control MDAH 087 cell cultures ceased growing by 37 population doublings (PD) and senesced. In contrast, one of six MDAH 087 cultures irradiated one to three times with x rays (2 or 4 Gy at 2 Gy/min) grew continuously for over 450 PD, indicating that the cells were immortal. All 12 WHE-7 cell cultures that were irradiated under the same conditions and all 20 unirradiated control WHE-7 cultures did not become immortal. Single-stranded DNA conformation analysis and DNA sequencing revealed that no additional mutations were induced by x-ray irradiation in exons 2-10 of the p53 gene of the immortal cells (LCS-4X2 cells) and that loss of the wild-type p53 gene was necessary but not sufficient for immortalization. Karyotypic analysis and chromosome painting analysis demonstrated that a high percentage (more than 98%) of LCS-4X2 cells had lost chromosome 6. Irradiation of WHE-7 cells nine times with x rays (2 Gy at 2 Gy/min) extended the cells' lifespans but did not immortalize them. These cells (X9 cells) exhibited a nonrandom karyotypic alteration, monosomy 6, that was confirmed by loss of heterozygosity for a polymorphic dinucleotide repeat sequence on chromosome 6. DNA analysis showed that X9 cells had no mutations in exons 2-10 of the p53 gene. DNA fingerprint analysis with a multi-locus probe detected DNA rearrangements in LCS-4X2 cells and X9 cells, indicating that both cells could have mutations at a gene or genes other than the p53 gene. The results are consistent with our previous findings that cells with a mutation in one gene involved in cellular senescence (i.e., the p53 gene in Li-Fraumeni fibroblasts) are prone to immortalization. Furthermore, we conclude that immortalization of normal human fibroblasts is a multistep process involving loss or inactivation of multiple genes, such as p53 and a gene on chromosome 6. Loss of a gene on chromosome 6 without p53 alterations extends cellular lifespan without immortalizing the cells.

Adult↗
PubMed1997

Anorectal malignant melanoma: report of a case.

A 74-year-old woman presented with anal bleeding and a protuberant mass. A biopsy of the mass revealed the proliferation of spindle-shaped cells with melanin pigments, and an abdominoperineal resection was performed, the histology of which confirmed malignant melanoma. Surgery was absolutely noncurative because massive metastases were encountered in the pelvic and paraaortic lymph nodes. However, postoperative chemotherapy, composed of decarbazine (DTIC), vincristine (VCR), and nimustine hydrochloride (ACNU), achieved satisfactory results. The patient has been well without any evidence of recurrence for more than 3 years.

Aged↗
PubMed1997

Determination of carcinogenic potential of mineral fibers by 8-hydroxydeoxyguanosine as a marker of oxidative DNA damage in mammalian cells.

8-Hydroxydeoxyguanosine (8-OH-dG) is a typical form of oxidative DNA damage, which causes mutations in vitro and in vivo. To develop a simple method of testing the carcinogenicity of fibrous materials, the formation of 8-OH-dG was determined in the DNA of J774 cells, an established reticulum cell sarcoma line, after treatment with various natural and man-made mineral fibers. The amount of 8-OH-dG was determined using high-pressure liquid chromatography (HPLC) equipped with an electrochemical detector (ECD). We tested three natural mineral fibers (crocidolite, amosite, and chrysotile) and three man-made mineral fibers (ceramic, glass, and potassium octatitanate). Among them, a significant increase in 8-OH-dG formation was observed in the crocidolite- and amosite-treated cells. We also measured the amount of tumor necrosis factor (TNF) produced by J774 cells incubated with the fibrous materials. Cellular TNF production increased after treatment with all the fibers tested, but it was not statistically significant except in the case of chrysotile. Therefore, these results indicate that the mechanism of TNF production is different from that of 8-OH-dG formation, and that the carcinogenicity of various fibrous materials can be better evaluated by measuring the 8-OH-dG level in J774 cellular DNA after treatment with these fibers.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Anti-mitogenic effects of sarpogrelate in cultured rat mesangial cells.

We investigated the effects of the new 5-HT2A receptor antagonist, sarpogrelate, on DNA synthesis in renal mesangial cells stimulated with 5-HT in the presence and absence of platelet-derived growth factor (PDGF)-BB. Both 5-HT and PDGF-BB demonstrated a mitogenic effect on these cells. When mesangial cells were incubated in the absence of PDGF-BB, sarpogrelate inhibited DNA synthesis in these cells in a dose-dependent manner. In the presence of PDGF-BB, sarpogrelate had a weaker anti-mitogenic effect in mesangial cells stimulated with 5-HT. Sarpogrelate was cytotoxic at concentrations over 10(-5) M according to the results of LDH release assays, and it reduced the S1 phase in mesangial cells stimulated with 5-HT by a flow cytometry. These findings suggest that sarpogrelate may be effective in the treatment of some glomerulonephritis associated with mesangial cell proliferation.

Animals↗
PubMed1997

Changes in plasma luteinizing hormone, testosterone and estradiol-17 beta levels and semen quality after injections of gonadotropin releasing hormone agonist and human chorionic gonadotropin in three dogs with oligozoospermia and two dogs with azoospermia.

Plasma luteinizing hormone (LH) and testosterone (T) levels in three normal male Beagles increased markedly, the LH levels peaking at 30 or 45 min and the T levels at 45 or 60 min respectively, after a subcutaneous injection of 1 microgram kg-1 gonadotropin releasing hormone agonist (GnRH-A). Two Collies and a Great dane diagnosed as oligozoospermic and two Shetland sheep dogs diagnosed as azoospermic by evaluation of semen quality were treated with 1 microgram kg-1 GnRH-A after blood collection. Their plasma levels of LH, T and estradiol-17 beta (E2) were measured by radioimmunoassay for the purpose of investigating the effect of hormone therapy on spermatogenic dysfunction and the mechanism on improvement of semen quality. The semen quality of one of the Collies had improved 4 weeks after the GnRH-A treatment. The dog was treated with GnRH-A again and mated with a bitch 4 days later. The bitch gave birth to five puppies. The other dogs, whose semen quality had not improved, were treated with an intramuscular injection of 500 or 1000 IU human chorionic gonadotrphin (hCG) per animal. Since the semen quality of the other Collie and the Great Dane improved temporarily 2 and 4 weeks, respectively, after hCG treatment, the former was mated with a bitch 5 days later. The bitch gave birth to a litter of seven puppies. These hormone treatments, however, had no effect on the azoospermia in the two Shetland sheep dogs. Although the mean plasma LH and T levels in the dogs with oligozoospermia had been low, their LH levels gradually increased after hormone treatment. There were no marked changes in plasma T or E2 levels. These findings indicate that the semen quality of dogs with oligozoospermia can be temporarily improved between 2 and 4 weeks after a single injection of GnRH-A or hCG and the fertility of the dogs restored by the injection.

Animals↗
PubMed1997

A defect in cell-to-cell adhesion via integrin-fibronectin interactions in a highly metastatic tumor cell line.

We investigated the role of integrin-fibronectin (FN) interactions in tumor cell adhesion. Two cloned tumor cell lines designated OV-LM (low-metastatic) and OV-HM (high-metastatic) were isolated from a murine ovarian carcinoma, OV2944. OV-LM and OV-HM cells exhibited high and low RGDS-sequence-dependent adhesiveness to FN, respectively. Both lines expressed comparable levels of alpha5 and alpha v integrins, which are capable of reacting with RGDS on FN. To compare the functions of these integrins between the two tumor lines, the signaling mechanism following FN stimulation was examined. Significant levels of phosphorylation of focal adhesion kinase (FAK) were detected in both OV-LM and OV-HM cells before FN stimulation. Whereas the level of FAK phosphorylation was appreciably enhanced in OV-LM cells stimulated with FN, stimulation of OV-HM cells with FN induced a reduction in the FAK phosphorylation in association with a significant decrease in the amount of FAK protein in the soluble compartment of cell lysates. A difference in the deposition of FN on the cell surface was also observed between the two types of tumor lines; OV-HM cells had an appreciably smaller amount of FN than OV-LM. Consistent with the functional abnormality of the integrin-FAK system and the smaller amount of FN on OV-HM, this clone exhibited a reduced cell-cell adhesion in the in vitro cell aggregation assay. Namely, OV-LM cells displayed a time-dependent increase in the formation of cell aggregates, whereas most OV-HM cells remained single. The formation of aggregates by OV-LM cells was inhibited by addition of RGDS peptide. These results indicate that the highly metastatic clone, OV-HM, exhibits a decreased capacity of cell-cell adhesion mediated by integrin-FN interactions and suggest that this defect is mainly due to the dysfunction of integrins/FAK rather than a decrease in the amount of integrins expressed on tumor cells.

Animals↗
PubMed1997

[Mechanisms of estrogen-induced carcinogenesis--detection of DNA adducts in cultured mammalian cells by 32P-postlabeling].

Estrogens are clearly carcinogenic in humans and rodents, but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays, but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system. Diethylstilbestrol (DES) and 17 beta-estradiol (E2) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. DNA adduct formation is detected in cells treated with DES, but not in cells treated with either alpha- or beta-dienestrol. Similarly, morphological transformation of SHE calls is induced by treatment with DES, but not by treatment with alpha- or beta-dienestrol. Exposure of SHE treatment cells to E2 and its metabolites 2-hydroxyestradiol and 4-hydroxyestradiol leads to covalent DNA adduct formation, corresponding to the induction of cell transformation. Induction of morphological transformation of SHE cells by estrogens correlates well with the ability of estrogens to induce DNA adduct formation. DNA damage caused by DNA adduct formation may be important in hormonal carcinogenesis. It is clear that hormones affect carcinogenesis by epigenetic mechanisms such as stimulation of cell proliferation of estrogen-dependent target cells and reprogramming of cellular differentiation and gene expression. In addition, significant evidence exists that certain estrogens can also cause genetic alterations by mechanisms not involving the classic estrogen receptor. These findings indicate that hormonal carcinogenesis is most likely a result of the interplay of both genetic and epigenetic factors.

Animals↗
PubMed1997

Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

Estrogens are clearly carcinogenic in humans and rodents but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system and our findings are summarized in this review. 17beta-Estradiol (E2) and diethylstilbestrol (DES) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. Treatment of the cells with E2 or DES fails to induce DNA damage, chromosome aberrations and gene mutations in SHE cells but results in numerical chromosome aberrations (aneuploidy) that could arise from microtubule disruption or disfunction of mitotic apparatus. Estrogen-induced genotoxicity is detected in cells following treatment with estrogen metabolites or following exogenous metabolic activation of estrogens. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. Both aneuploidy induction and DNA damage caused by DNA adduct formation correlate with the estrogen-induced cell transformation and may be important in hormonal carcinogenesis. We propose that multiple effects of estrogens acting together cause genetic alterations leading to cell transformation.

Aneuploidy↗
PubMed1996

Mechanism of Phreatic Eruptions at Aso Volcano Inferred from Near-Field Broadband Seismic Observations

Broadband seismometers deployed at Aso volcano in Japan have detected a hydrothermal reservoir 1 to 1.5 kilometers beneath the crater that is continually resonating with periods as long as 15 seconds. When phreatic eruptions are observed, broadband seismograms elucidate a dynamic interplay between the reservoir and discharging flow along the conduit: gradual pressurization and long-period (approximately20 seconds) pulsations of the reservoir during the 100 to 200 seconds before the initiation of the discharge, followed by gradual deflation of the reservoir concurrent with the discharging flow. The hydrothermal reservoir, where water and heat from the deeper magma chamber probably interact, appears to help control the surface activity at Aso volcano.

Journal Article↗
PubMed1996

Estrogen-induced cell transformation and DNA adduct formation in cultured Syrian hamster embryo cells.

To study the possible involvement of DNA damage in cell transformation induced by estrogens, we examined whether DNA adduct formation is elicited in cultured Syrian hamster embryo (SHE) cells treated with estrogens and their derivatives by means of the 32P-postlabeling assay. Morphological transformation of the cells was induced by treatment with diethylstilbestrol (DES) at 1-10 micrograms/mL for 24 h but not by treatment with its derivatives trans, trans-dienestrol (alpha-DIES) or cis, cis-dienestrol (beta-DIES) at 1-10 micrograms/mL for 24 h. Similarly, DNA adduct formation was elicited by exposure of SHE cells to DES at 1-10 micrograms/mL for 24 h but not by either alpha-DIES or beta-DIES. Treatment of SHE cells with DES at 1-10 micrograms/mL for 2 h in the presence of exogenous metabolic activation with rat liver post-mitochondrial supernatant enhanced morphological transformation in a dose-dependent manner. Our previous studies have demonstrated that exposure of SHE cells to DES under the same conditions with exogenous metabolic activation induces somatic mutations at the Na+/K+ ATPase locus. Therefore, we examined whether with exogenous metabolic activation DES induced DNA adduct formation in SHE cells. DNA adducts were not detected when SHE cells were treated with DES at 1-10 micrograms/mL for 2 h in the presence of exogenous metabolic activation. Treatment with 17 beta-estradiol (E2), 2-hydroxyestradiol (2-OH E2), or 4-hydroxyestradiol (4-OH E2) at 1 microgram/mL for 24 h induced DNA adduct formation in the cells, in parallel with the induction of cell transformation. The rank order of DNA adduct formation was 4-OH E2 > 2-OH E2 > E2. The results indicate that estrogens induce DNA adduct formation in cultured SHE cells, but the induction may not be the only mechanism relevant to the initiation of cell transformation.

Animals↗
PubMed1996

Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture.

The US National Toxicology Program has shown equivocal evidence of carcinogenic activity of sodium fluoride (NaF) in male F344/N rats based on the occurrence of five osteosarcomas in treated animals. In the study the osteosarcomas developed mainly in the rat vertebrae. To provide a possible mechanistic basis for the observed tumors, the genotoxic effects of NaF on the possible target organ of NaF carcinogenesis were examined. Rat vertebral body-derived (RVBd) cells were established from trabecular bone of vertebral bodies of a male F344/N rat 6 weeks of age and treated with NaF. RVBd cells in secondary culture exhibited a high level of alkaline phosphatase (ALP) activity when the cells at confluence were assayed by ALP staining. When the histochemical examination was performed on RVBd cell colonies, most of the colonies were stained positively for ALP. Confluent RVBd cells were responsive to 10(-8) M 1 alpha.25-dihydroxyvitamin D3 with a 7.7-fold increase in osteocalcin production over base line values. The von Kossa staining demonstrated that in the presence of 2 mM beta-glycerophosphate, RVBd cells that were allowed to grow past confluence for approximately 2 months formed mineralized nodules. When RVBd cells in tertiary culture were treated with NaF at 0.5-2.0 mM for 24-72 h, the growth and/or survival of the treated cells was reduced in a dose-dependent manner. Significant increases in the frequencies of chromosome aberrations were induced in a dose- and treatment time-dependent fashion when NaF was administered to RVBd cells at 0.5 and 1.0 mM for 24 and 48 h. The results indicate that NaF is genotoxic to rat vertebrae, providing a possible mechanism for the vertebrae, as a target organ of NaF carcinogenesis.

Animals↗
PubMed1996

Molecular mechanisms underlying IFN-gamma-mediated tumor growth inhibition induced during tumor immunotherapy with rIL-12.

The present study investigates the molecular mechanisms by which IFN-gamma produced as a result of in vivo IL-12 administration exerts its anti-tumor effects. rIL-12 was administered three or five times into mice bearing CSA1M fibrosarcoma, OV-HM ovarian carcinoma or MCH-1-A1 fibrosarcoma. This regimen induced complete regression of CSA1M and OV-HM tumors but only transient growth inhibition of MCH-1-A1 tumors. The anti-tumor effects of IL-12 were associated with enhanced induction of IFN-gamma because these effects were abrogated by pretreatment of hosts with anti-IFN-gamma antibody. Exposure in vitro of the three types of tumor cells to rRFN-gamma resulted in moderate to potent inhibition of tumor cell growth. IFN-gamma stimulated the expression of mRNAs for an inducible type of NO synthase (iNOS) in CSA1M cells and indoleamine 2,3-dioxygenase (IDO), an enzyme capable of degrading tryptophan, in OH-HM cells, but induced only marginal levels of these mRNAs in MCH-1-A1 cells. In association with iNOS gene expression, IFN-gamma-stimulated CSA1M cells produced a large amount of NO which functioned to inhibit their own growth in vitro. Although OV-HM and MCH-1A1 cells did not produce NO, they also exhibited NO susceptibility. Whereas the tumor masses from IL-12-treated CSA1M-bearing or OV-HM-bearing mice induced higher levels of iNOS (for CSA1M) or IDO and iNOS (for OV-HM) mRNAs, the MCH-1-A1 tumor mass expressed lower levels of iNOS mRNA alone. Moreover, massive infiltration of CD4(+) and CD8(+) T cells and Mac-1(+) cells was seen only in the CSA1M and OV-HM tumors. Thus, these results indicate that IFN-gamma produced after IL-12 treatment induces the expression of various genes with potential to modulate tumor cell growth by acting directly on tumor cells or stimulating tumor-infiltrating lymphoid cells and that the effectiveness of IL-12 therapy is associated with the operation of these mechanisms.

Animals↗
PubMed1996

Inhibition of growth and metastasis of ovarian carcinoma by administering a drug capable of interfering with vascular endothelial growth factor activity.

The present study investigates the relationship between in vivo growth/metastasis of tumor cells and their capacity to produce the vascular endothelial growth factor (VEGF), as well as the regulation of tumor growth/metastasis using an angiogenesis-inhibitory drug. Two cloned tumor cell lines designated OV-LM and OV-HM were isolated from a murine ovarian carcinoma OV2944. OV-LM and OV-HM cells grew in cultures at comparable rates. However, when transplanted s.c. into syngeneic mice, OV-HM exhibited a faster growth rate and a much higher incidence of metastasis to lymph nodes and lung. Histologically, intense neovascularization was detected in sections of OV-HM but not of OV-LM tumor. OV-HM and OV-LM tumor cells obtained from in vitro cultures expressed high and low levels of VEGF mRNA, respectively. A difference in VEGF mRNA expression was much more clearly observed between RNAs prepared from fresh OV-HM and OV-LM tumor masses: RNA from OV-HM contained larger amounts of VEGF mRNA, whereas RNA from OV-LM exhibited only marginal levels of VEGF mRNA. An angiogenesis-inhibitory drug, FR118487 inhibited the VEGF-mediated in vitro growth of endothelial cells but did not affect the expression in vitro of VEGF mRNA by OV-HM tumor cells. Intraperitoneal injections of FR118487 into mice bearing OV-HM tumors resulted in: (i) a subsequent growth inhibition of primary tumors; (ii) a marked decrease in neovascularization inside tumor masses expressing comparable levels of VEGF mRNA to those detected in control OV-HM masses; and (iii) almost complete inhibition of metastasis to lymph nodes and lung. These results indicate that growth/metastasis of tumor cells correlates with their VEGF-producing capacity and that an angiogenesis inhibitor, FR118487, inhibits tumor growth and metastasis through mechanism(s) including the suppression of VEGF function in vivo.

Animals↗