共查询到20条相似文献,搜索用时 46 毫秒
1.
We determined whether lyophilized High Five (H5) insect cells engineered to produce IFN-beta (H5BVIFN-beta) could induce systemic immunity against occult brain metastases. C3H/HeN mice were injected s.c. with syngeneic UV-2237M fibrosarcoma or K-1735M2 melanoma cells. Intralesional injection of 2 x 10(6) lyophilized H5BVIFN-beta cells produced complete regression of the s.c. tumors. Six weeks later, UV-2237M fibrosarcoma cells or K-1735M2 melanoma cells were injected into the internal carotid artery of naive or treated mice. UV-2237M brain metastases developed in naive mice or mice cured of K-1735M2 tumors but not in mice cured of UV-2237M tumors. Similarly, K-1735M2 brain metastases developed in naive mice or mice cured of UV-2237M fibrosarcomas but not in mice cured of K-1735M2 melanoma. In the next set of studies, mice were injected s.c. with UV-2237M fibrosarcoma cells. On day 7, UV-2237M fibrosarcoma cells or K-1735M2 cells were implanted into the internal carotid artery, and on day 10, the s.c. tumors were injected with lyophilized H5BVIFN-beta. Both the s.c. tumors and the occult brain metastases produced from carotid injections were eradicated in a tumor-specific manner. The regression of the brain metastases was abrogated by depletion of CD4(+) or CD8(+) cells from immunized mice. These results demonstrate that specific systemic immunity can be induced by lyophilized H5BVIFN-beta and that the resultant immune response can eliminate established brain metastasis. 相似文献
2.
The metastatic behavior of a murine fibrosarcoma (UV-2237M-ADMR) resistant to Adriamycin (ADM) (doxorubicin) was investigated. Subclones isolated from the UV-2237M-ADMR line, which originated from a single colony, generally displayed a similar degree of resistance to ADM (eight out of nine clones did not differ from this UV-2237M-ADMR line). In contrast, they differed significantly in their capacity to form lung colonies after i.v. injection (six of nine clones differed significantly from the UV-2237M-ADMR line, p less than or equal to 0.005, Mann-Whitney U test). The UV-2237M-ADMR cell line maintained resistance to ADM even after 17 weeks of growth in syngeneic mice, although a gradual decrease in resistance was observed over this time. Spontaneous metastases from the UV-2237M-ADMR tumor commonly retained resistance to ADM. Of 18 cell lines, each established from an individual lung nodule, 16 showed plating efficiencies in the presence of ADM comparable to that of the primary UV-2237M-ADMR tumor. The remaining two lines had partially reverted to the sensitive state. The i.v. administration of ADM significantly reduced the lung tumor burden of mice with ADM-sensitive UV-2237M tumors but failed to affect the lung tumor burden of mice with UV-2237M-ADMR tumors. The UV-2237M-ADMR tumor line, exhibiting as it does both drug-resistant and metastatic behavior, provides a useful model system with which to investigate the metastatic process and the development of drug resistance. 相似文献
3.
The relationship between nitric oxide synthase II (NOS II) inducibility and the metastatic ability of UV-2237 murine fibrosarcoma cells was determined. Highly metastatic cells survived to produce numerous lung metastases after i.v. injection in syngeneic C3H/HeN mice, whereas poorly metastatic cells did not. Highly metastatic clones exhibited higher levels of NOS II than did poorly metastatic clones in response to interleukin 1alpha and IFN-gamma stimulation. Furthermore, both poorly and highly metastatic clones contained an identical p53 mutation. Overexpression of NOS II in a highly metastatic clone by transfection with NOS II gene retarded tumor growth and completely suppressed metastasis. Our data indicate that a low to moderate level of NOS II expression directly correlates with metastatic ability of UV-2237 fibrosarcoma cells carrying mutant p53 and that a high level of nitric oxide production suppresses tumor growth and metastasis. 相似文献
4.
C Wilmanns D Fan C A O'Brian C D Bucana I J Fidler 《International journal of cancer. Journal international du cancer》1992,52(1):98-104
We determined the effects of organ environment on the response of murine CT-26 colon carcinoma cells to 2 structurally and pharmacologically distinct chemotherapeutic agents. CT-26 cells were injected i.v. (to produce lung lesions), s.c., into the cecal wall, and into the spleen (to produce spleen and liver lesions). Doxorubicin (DXR) at 10 mg/kg, 5-fluorouracil (5-FU) at 20 mg/kg, or saline (control) was injected intravenously on different schedules after tumor-cell implantation. The in vivo responses of the tumors growing in the cecum, spleen, liver, lung and subcutis were compared. Colon carcinomas growing in the subcutis were most sensitive to DXR. Tumors growing in the spleen and cecum were most sensitive to 5-FU and less so to DXR. Tumors in the liver were highly resistant to both drugs, whereas experimental lung metastases were sensitive to 5-FU but resistant to DXR. The differential responses of the tumors to the drugs were not due to drug distribution. The level of protein-kinase-C activity was elevated in the spleen, liver and cecum tumors as compared with s.c. tumors and correlated with the in vivo DXR resistance of the tumor cells. This correlation suggested that organ environment may modulate the chemosensitivity of tumor cells, at least in part, by perturbing signal transduction pathways. Collectively, the data indicate that the organ environment has profound effects on the response of tumor cells to chemotherapy. A molecular understanding of this phenomenon should facilitate the design of more effective systemic chemotherapy for cancer metastases. 相似文献
5.
Lu W Dong Z Donawho C Fidler IJ 《International journal of cancer. Journal international du cancer》2002,100(4):480-485
We investigated the efficacy of a preparation containing High Five (H5) insect cells infected with recombinant baculovirus encoding the murine interferon-beta gene (H5BVIFN-beta) against established primary tumors and occult lung metastases. Injection of live or lyophilized H5BVIFN-beta into established subcutaneous tumors of the highly metastatic murine UV-2237m fibrosarcoma or K-1735M2 melanoma in syngeneic mice eradicated both primary tumors and preexisting lung metastases. The therapeutic effects of H5BVIFN-beta were not observed in nude mice and were diminished in syngeneic mice depleted of CD4(+) and CD8(+) T cells. Immunohistochemical staining showed that tumors injected with H5BVIFN-beta were densely infiltrated by CD4(+) and CD8(+) T cells in mice with normal CD4/CD8 complement. These data demonstrate that, unlike most immunologic approaches in which prophylaxis can be achieved but eradication of established tumor is rare, lyophilized preparations of H5BVIFN-beta can serve as a novel immunotherapy against both primary tumors and their occult metastases. 相似文献
6.
Specific activators of protein kinase C (PKC), including the phorbol-ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), can reduce the chemosensitivities of a variety of mammalian tumor cell lines and their cytotoxic drug-selected multidrug resistant (MDR) variants to MDR-linked drugs, thus implicating PKC in the MDR phenotype. Previously, we reported that the adriamycin-selected MDR murine fibrosarcoma cell line UV-2237M-ADRR has approximately twice as much PKC activity as the parental UV-2237M line. In this report, we show that the level of [3H]phorbol-12,13-dibutyrate specific binding activity was elevated 3.5-fold in the MDR cells, thus establishing that phorbol-ester responsive PKC is overexpressed in the MDR line. Phorbol esters mediate downregulation of PKC by stimulating proteolysis of the enzyme, without altering the rate of PKC synthesis. We report that the kinetics of TPA-induced downregulation of PKC activity differ markedly in parental and MDR UV-2237M cells, providing evidence that the overexpression of phorbol-ester responsive PKC in adriamycin-selected MDR UV-2237M-ADRR cells results, at least in part, from a reduced rate of PKC degradation in the cells. 相似文献
7.
The potency of chloroaluminum sulfonated phthalocyanine (ClAlSPc) as a photosensitizing agent for photodynamic therapy of cancer was evaluated in vivo by its ability to be taken up and retained by murine tumors of diverse histological origin. Antitumor effects following laser irradiation were evaluated by measurement of the tumor weights of dissected-out tumor masses. Three tumors (Colo 26, a colorectal carcinoma; M5076, a reticulum cell sarcoma; and UV-2237, a fibrosarcoma) growing s.c. in the flank region retained substantially greater quantities of ClAlSPc than did adjacent skin and muscle achieving peak values 24-48 h after the i.v. administration of ClAlSPc (10 mg/kg). The relative magnitude of ClAlSPc retention by these tumors was Colo 26 greater than M5076 greater than UV-2237. However, normal liver and spleen were organs which retained the greatest amounts of ClAlSPc even compared to the s.c. grown tumors and other normal tissues examined. Flow cytometric analysis of tumor cell suspensions obtained from collagenase-digested tumors showed that individual neoplastic cells were capable of taking up and retaining ClAlSPc. Photodynamic therapy, undertaken by i.v. administration of dye (5 mg/kg) followed 24 h later by local laser light irradiation (675 nm, 100 J), brought about significant (Colo 26, M5076, and 3LL tumors) and obvious but nonsignificant (UV-2237 tumor) reductions in tumor weights, as assessed 5 days later. Thus, selective tumor retention of ClAlSPc coupled with a significant response to red light produced dramatic alterations in cancer growth. 相似文献
8.
Fan D Poste G Ruffolo R Dong Z Seid C Earnest L Campbell T Clyne R Beltran P Fidler I 《International journal of oncology》1994,4(4):789-798
The purpose of this study was to determine whether agonists and antagonists of alpha-adrenoceptors that affect calcium fluxes and protein kinase C signal transduction alter the chemosensitivity of cancer cells that exhibit multidrug resistance (MDR). The effects of nine alpha-adrenoceptor antagonists or antagonists on the in vitro chemosensitivity of the UV-2237 murine fibrosarcoma and its doxorubicin-selected MDR variants (UV-2237-R1 and UV-2237-R10) were examined. Noncytotoxic concentrations of the alpha-adrenoceptor antagonist furobenzazepine enhanced the antitumor activity of doxorubicin, actinomycin D, vinblastine and vincristine, but not 5-fluorouracil. Similar effects of furobenzazepine were also observed in recently established doxorubicin-resistant MDR variants of the CT-26 murine colon carcinoma. The chemosensitizing effect of furobenzazepine was associated with an increase in intracellular accumulation of anticancer drugs. Furobenzazepine did not compete with [H-3]azidopine for photoaffinity labeling of P-glycoprotein, but it did produce a transient 30% reduction of P-glycoprotein in the MDR cells. These data indicate that furobenzazepine can reverse a P-glycoprotein-mediated experimental MDR phenotype. 相似文献
9.
Fan D Poste G Obrian C Seid C Ward N Earnest L Fidler I 《International journal of oncology》1992,1(7):735-742
A variety of resistance phenotypes to cytotoxic agents in bacteria, protozoa parasites and mammalian cells are mediated by evolutionarily conserved proteins of the mdr family. The finding that chloroquine resistance in the malarial parasite, Plasmodium falciparum, that is mediated by an mdr-1 gene product can be circumvented by tricyclic antidepressant drugs has stimulated the present study to assess whether this class of agents might also modulate the multidrug resistance (MDR) phenotype(s) in mammalian tumor cells. The possible chemosensitizing effects of nine antidepressant drugs have been tested against the UV-2237M murine fibrosarcoma line and its MDR variant. At nontoxic concentrations all nine antidepressants markedly enhanced the cytotoxicity of ADR against the parental cells but were much less effective against the MDR cells. The most active antidepressant, trazodone, also enhanced the cytotoxicities of vinblastine and vincristine, but not those of actinomycin D, mitomycin C, or 5-fluorouracil. The parental cells treated with trazodone exhibited an increased accumulation of intracellular ADR, but lacked detectable alterations in the expression and drug-binding activity of plasma membrane P-glycoprotein, and trazodone did not affect the activities of isolated protein kinase C and calmodulin. These data suggest that the antidepressant drug trazodone may be useful in the reversal of the intrinsic drug resistance of tumor cells that express low levels of P-glycoprotein. 相似文献
10.
Variant cell lines of the murine fibrosarcoma UV-2237, selected for doxorubicin [adriamycin (ADM)] resistance, were used to study the tumoricidal activity of macrophages that had been exposed to ADM. Free ADM (0.01-1 microgram/ml) was cytotoxic to the sensitive UV-2237M parent and to the partially sensitive UV-2237M-revertant cell lines, whereas the ADM-resistant UV-2237M ADMR line was unaffected by these levels of ADM. Macrophages harvested from the peritoneal cavities of mice given ip injections of 10 mg ADM/kg body weight 1 day or 4 days previously inhibited proliferation of the 3 cell lines, an effect that was directly correlated to the degree of ADM sensitivity of each cell line. Macrophages exposed in vitro to ADM (from 0.01 to 1 microgram/ml) inhibited the growth of, and eventually were cytolytic to, the parent and the revertant cell lines; these ADM-exposed macrophages did not affect the UV-2237M-ADMR cell line. The correlation between the antitumor effects of macrophages exposed to ADM and the ADM susceptibility of tumor cells suggests that ADM-exposed macrophages exert their effect by the release or transfer of the stored drug. 相似文献
11.
Enhancement of murine tumor cell sensitivity to adriamycin by presentation of the drug in phosphatidylcholine-phosphatidylserine liposomes 总被引:1,自引:0,他引:1
In vitro incubation of mouse UV-2237M fibrosarcoma cells with liposomes containing Adriamycin (ADR) produced significant cytotoxicity in drug-sensitive cells and in multidrug-resistant variants of this tumor. ADR was encapsulated in the aqueous space of multilamellar liposomes composed of phosphatidylcholine and phosphatidylserine. The preparation was stable in medium at 37 degrees C for up to 7 days. Free unencapsulated ADR produced cytostasis in parental ADR-sensitive cells but not in variant lines selected for resistance to the drug. In contrast, ADR encapsulated in multilamellar liposomes (MLV) produced high levels of cytostasis in both ADR-sensitive and ADR-resistant cells. The phospholipid composition of the MLV influenced the outcome of ADR-mediated cytostasis. ADR encapsulated in MLV consisting of only phosphatidylcholine did not produce cytostasis. Increasing the proportion of phosphatidylserine in the MLV increased the level of ADR-mediated cytotoxicity in cells resistant to free ADR. This effect was not due to simple modification of tumor cell surface by liposomes since ADR added to resistant cells together with liposomes containing buffer produced less cytostasis. The cytostasis of resistant cells by ADR in liposomes was not due to appreciable changes in the intracellular ADR concentration or localization within the cells because ADR-induced DNA cleavage was not found in ADR-resistant cells treated with cytostatic amounts of liposomal ADR. Whether the enhanced sensitivity of tumor cells to ADR was due to localized damage to the plasma membrane through a phosphatidylserine-mediated release of the drug to the cell surface is now under active investigation. 相似文献
12.
Skin cancers induced in mice by UV radiation often exhibit a regressor phenotype. In order to determine how tumors escape the immune defenses of the normal immunocompetent host, we sought to isolate progressor variants from a UV radiation-induced C3H mouse regressor fibrosarcoma cell line, UV-2240, by transfection with an activated Ha-ras oncogene. A cotransfection protocol using pSV2-neo DNA, which confers resistance to the antibiotic G418, was used to select transfected cells. Injection of Ha-ras-transfected UV-2240 cells s.c. into immunocompetent C3H mice produced tumors in four of 36 animals. In contrast, UV-2240 cells transfected with pSV2-neo DNA alone or mock transfected with CaPO4 did not produce tumors in normal C3H mice. DNAs from cell lines established from Ha-ras-induced tumors contained unique Ha-ras sequences in addition to those sequences endogenous to UV-2240 cells. However, the Ha-ras-induced progressor variants did not overexpress the Mr 21,000 protein. The Ha-ra-induced progressor variants produced experimental lung metastasis in both normal C3H and nude mice, although they induced more lung nodules in nude mice than in normal C3H mice. In addition, all four Ha-ras-induced progressor variants produced significantly more experimental lung metastases in nude mice than did the parent UV-2240 cell line. However, both the parental UV-2240 cell line and the Ha-ras-induced progressor variants expressed similar levels of H-2Kk and H-2Dk antigens and were immunologically cross-reactive, as determined by in vitro cytotoxic T-lymphocyte and in vivo immunization-challenge assays. These results indicate that the progressor phenotype of the Ha-ras-induced tumor variants is not due to loss of tumor-specific transplantation or Class I major histocompatibility complex antigens. This implies that some tumor cells can escape the immune defenses of the normal immunocompetent host by mechanisms other than loss of tumor-specific transplantation and Class I major histocompatibility antigens. 相似文献
13.
A variant cell line (UV-2237-ADMR) resistant to the anthracycline antibiotic Adriamycin (Doxorubicin) was selected in vitro from the murine UV-2237 fibrosarcoma tumor cell line. Resistance to Adriamycin proved to be a stable characteristic of the UV-2237-ADMR line, whether the line was grown in vivo or in vitro. The UV-2237-ADMR line also exhibited increased resistance to N-trifluoroacetyladriamycin-24-valerate, daunorubicin, actinomycin D, amsacrine, mitomycin C, vinblastine, and vincristine but not to bleomycin. Cell-cell hybridization studies showed that the Adriamycin resistance is an incompletely dominant trait. Uptake and efflux studies with [14C]Adriamycin indicated that the resistance exhibited by the UV-2237-ADMR line was due to both reduced uptake of the drug and an increased active efflux. 相似文献
14.
Evidence for the role of 34-kDa galactoside-binding lectin in transformation and metastasis 总被引:21,自引:0,他引:21
A Raz D G Zhu V Hogan N Shah T Raz R Karkash G Pazerini P Carmi 《International journal of cancer. Journal international du cancer》1990,46(5):871-877
The endogenous Mr 34,000 galactoside-binding lectin (L-34) is found at elevated levels in a wide variety of neoplastic cells and correlative evidence suggests that it is involved in tumor metastasis in vivo and in transformation in vitro. We demonstrate here that introduction of recombinant L-34 into tumorigenic, weakly metastatic UV-2237-cl-15 fibrosarcoma cells results in an increased incidence of experimental lung metastases in syngeneic and nude mice. Transfection of normal BALB/c-A31 cloned fibroblasts with functional L-34 results in acquisition of anchorage-independent growth and in morphological transformation in vitro but not in tumorigenicity in vivo. These results provide direct evidence that the cellular expression of L-34 is associated with some aspects of transformation and with metastasis, but not with tumorigenicity per se. 相似文献
15.
Inhibition of experimental tumor metastasis by selective activation of natural killer cells 总被引:6,自引:0,他引:6
N Hanna 《Cancer research》1982,42(4):1337-1342
The antitumor activity generated by selective activation of natural killer (NK) cells was studied in vitro and in vivo. Unlike Corynebacterium parvum CN6134, which activated both NK cells and macrophages, periodate-oxidized C. parvum CN6134 lost the ability to activate macrophages but retained almost all the NK-stimulating capacity of the untreated bacterium. The "inactive" C. parvum strain CN5888 also induced a modest, but selective, activation of NK cells. The enhanced NK cell-mediated cytotoxicity was expressed against YAC-1 lymphoma, UV-2237 fibrosarcoma, and B16 melanoma target cells in vitro and was manifested in vivo by increased destruction of circulating tumor cells and the inhibition of hematogenous tumor metastasis. Periodate-treated C. parvum was as effective in inhibiting the formation of B16 melanoma pulmonary metastases as was untreated C. parvum. In both cases, the inhibiting effect corresponded closely with the kinetics of NK cell activation. 相似文献
16.
M R Bani A Garofalo E Scanziani R Giavazzi 《Journal of the National Cancer Institute》1991,83(2):119-123
Experiments were done to determine the effect of interleukin-1-beta (IL-1 beta) on metastasis formation in different tumor systems. Intravenous administration of 1 microgram of human recombinant IL-1 beta given 1 hour before tumor cell injection augmented lung colony formation (experimental metastases) by the human A375 melanoma variants, the human HT-29M colon carcinoma, the SN12-K1 renal carcinoma in nude mice, the murine B16 melanoma variants, and the murine UV-2237M fibrosarcoma in syngeneic recipients. The same treatment did not induce lung colony formation by a human rectal carcinoma (HCC-P2988) or by a murine reticulum cell sarcoma (M5076), both of which are not metastatic to the lung. Spontaneous metastases were studied in C57BL/6 mice bearing the B16-BL6 melanoma (metastatic to the lung) in their footpad and the M5076 reticulum cell sarcoma (metastatic to the liver) subcutaneously. Daily intraperitoneal treatment with 1 microgram of IL-1 beta increased lung and liver metastases. These findings indicate that treatment of mice with IL-1 beta can increase the number of artificial or spontaneous metastases and that this effect is not limited to a single tumor type or to a specific organ. 相似文献
17.
Gohji K Nakajima M Dinney C Fan D Pathak S Killion J Voneschenbach A Fidler I 《International journal of oncology》1993,2(1):23-32
We established a new human renal cell carcinoma system to study some properties of metastatic renal cancer cells and the influence of the organ environment on their metastatic potential. Renal cell carcinoma obtained from a surgical specimen was dissociated enzymatically. Cells were injected into the subcutis, kidney, cecal wall, and spleen of nude mice. Tumors grew in the subcutis and kidney. Only kidney tumors produced distant metastasis. Subcutaneous tumors were avascular and encapsulated, whereas kidney tumors were highly vascularized and invaded the kidney parenchyma. Cell lines were also established from several spontaneous lung metastases. The most metastatic cell line (LM-6) expressed higher levels of basic fibroblast growth factor, gelatinase, and urokinase activity. These results show that human neoplasms are heterogeneous for biologic properties, that orthotopic implantation is essential for the selection, growth, and metastasis of human renal cell carcinoma cells, and that metastatic cells must possess multiple properties to enable them to complete the process. 相似文献
18.
Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: effect of estrogen and progesterone. 总被引:4,自引:0,他引:4
B E Elliott S P Tam D Dexter Z Q Chen 《International journal of cancer. Journal international du cancer》1992,51(3):416-424
Previously we have shown that a murine mammary carcinoma cell line, designated SPI, grows and metastasizes more efficiently in the mammary gland than in the subcutis. In this report, we examine the tissue specificity of this phenomenon. Our results show that SPI cells grow best in the mesenteric and ovarian fat pads and well in the mammary gland, but very poorly in the subcutis or peritoneal cavity. Massive dissemination of tumors from the ovarian and mesenteric sites occurs to the liver, spleen and diaphragm. In contrast, metastases from the mammary site occur primarily in the lung. Co-transplantation of a threshold number of SPI cells with mammary or ovarian fat fragments into the subcutis results in increased tumor growth, whereas very few tumors form in sham controls receiving no fat fragments. Removal of the ovaries of donor and recipient mice abrogates tumor growth in adipose tissue transplants. Estrogen can stimulate growth of SPI in adipose tissue sites, whereas progesterone inhibits growth. In contrast, in vivo growth of a stable metastatic variant selected from SPI cells was not inhibited by progesterone. SPI cells growing in ovarian and mesenteric fat pads showed increased expression of estrogen receptors and progesterone receptors, as well as detectable levels of epidermal-growth-factor receptors, whereas receptor levels decreased to baseline on tumors in the subcutis. The levels of estrogen-receptor mRNA reflect the corresponding functional expression of receptors; this finding suggests that the regulation of estrogen-receptor expression in this system is, at least in part, at the mRNA level. Our results are consistent with the model that adipose tissue exerts an estrogen-dependent positive regulatory effect on primary SPI tumor growth, and promotes the formation of metastases. 相似文献
19.
Comparative studies on the quantitative analysis of experimental metastatic capacity 总被引:1,自引:0,他引:1
The purpose of these studies was to establish a procedure for determining the relative experimental metastatic potential of unrelated murine tumors. We used three tumors (the B16-F10 melanoma, which is syngeneic to the C57BL/6N mouse, and the K-1735 melanoma and the UV-2237 fibrosarcoma, which are syngeneic to the C3H/HeN mouse). Various numbers of tumor cells were injected into normal or immunosuppressed syngeneic recipients and into 3-week-old BALB/c nude mice. At appropriate intervals, the recipient mice were killed, and the metastatic burden was determined. The number of experimental metastases was not linearly correlated with cell input. Thus, simply comparing the incidence of metastasis resulting from the injection of one predetermined dose of tumor cells did not allow for determination of their relative metastatic capacities. More reproducible and meaningful results were obtained by introducing increasing numbers of viable tumor cells admixed with a constant number of nontumorigenic (X-irradiated) tumor cells serving as carrier. The incidence of metastasis by few or many injected cells is influenced by host factors such as immune status, and therefore determinations of the true metastatic nature of any given tumor necessitate the choice of an appropriate recipient. 相似文献
20.
We determined whether an adenoviral vector-mediated murine IFN-beta gene therapy could eradicate established s.c. tumors produced by murine UV-2237m fibrosarcoma cells. The tumor cells were highly susceptible to infection by adenoviral vectors. Cells infected with 10 or 100 multiplicity of infection of AdCIFN-beta, an adenoviral vector encoding murine IFN-beta driven by the human cytomegalovirus promoter, expressed high levels of steady-state IFN-beta mRNA and produced 500 or 7,000 units of IFN-beta activity/10(6) cells/24 h, respectively. Infection of tumor cells with 30 multiplicity of infection of AdCIFN-beta (but not control AdCLacZ vector) inhibited in vitro tumor cell proliferation by 40-45%. Intralesional injection of 5 x 10(8) plaque-forming units of AdCIFN-beta (but not AdLacZ) eradicated established s.c. fibrosarcomas in syngeneic mice but not fibrosarcomas in nude mice. Mice cured of the disease developed systemic immunity against rechallenge with UV-2237m cells but not against another syngeneic tumor, the K-1735 M2 melanoma. Immunohistochemical analysis revealed that tumors injected with AdCIFN-beta contained more macrophages and CD4+ and CD8+ cells than did tumors injected with AdCLacZ or saline. Most cells in the PBS- and AdCLacZ-treated tumors stained positive for proliferating cell nuclear antigen, and few cells stained for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling. In sharp contrast, AdCIFN-beta-treated tumors contained few proliferating cell nuclear antigen-positive cells and many terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-positive cells. Taken together, our data demonstrate that IFN-beta gene therapy delivered by adenoviral vectors can be effective against fibrosarcomas. 相似文献