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1.
Buchegger F Adamer F Schaffland AO Kosinski M Grannavel C Dupertuis YM de Tribolet N Mach JP Delaloye AB 《International journal of cancer. Journal international du cancer》2004,110(1):145-149
Intratumoural (i.t.) injection of radio-iododeoxyuridine (IdUrd), a thymidine (dThd) analogue, is envisaged for targeted Auger electron- or beta-radiation therapy of glioblastoma. Here, biodistribution of [(125)I]IdUrd was evaluated 5 hr after i.t. injection in subcutaneous human glioblastoma xenografts LN229 after different intravenous (i.v.) pretreatments with fluorodeoxyuridine (FdUrd). FdUrd is known to block de novo dThd synthesis, thus favouring DNA incorporation of radio-IdUrd. Results showed that pretreatment with 2 mg/kg FdUrd i.v. in 2 fractions 0.5 hr and 1 hr before injection of radio-IdUrd resulted in a mean tumour uptake of 19.8% of injected dose (% ID), representing 65.3% ID/g for tumours of approx. 0.35 g. Tumour uptake of radio-IdUrd in non-pretreated mice was only 4.1% ID. Very low uptake was observed in normal nondividing and dividing tissues with a maximum concentration of 2.9% ID/g measured in spleen. Pretreatment with a higher dose of FdUrd of 10 mg/kg prolonged the increased tumour uptake of radio-IdUrd up to 5 hr. A competition experiment was performed in FdUrd pretreated mice using i.t. co-injection of excess dThd that resulted in very low tumour retention of [(125)I]IdUrd. DNA isolation experiments showed that in the mean >95% of tumour (125)I activity was incorporated in DNA. In conclusion, these results show that close to 20% ID of radio-IdUrd injected i.t. was incorporated in tumour DNA after i.v. pretreatment with clinically relevant doses of FdUrd and that this approach may be further exploited for diffusion and therapy studies with Auger electron- and/or beta-radiation-emitting radio-IdUrd. 相似文献
2.
Fluorodeoxyuridine improves imaging of human glioblastoma xenografts with radiolabeled iododeoxyuridine. 总被引:3,自引:0,他引:3
Y M Dupertuis M Vazquez J P Mach N De Tribolet C Pichard D O Slosman F Buchegger 《Cancer research》2001,61(21):7971-7977
Use of radiolabeled nucleotides for tumor imaging is hampered by rapid in vivo degradation and low DNA-incorporation rates. We evaluated whether blocking of thymidine (dThd) synthesis by 5-fluoro-2'-deoxyuridine (FdUrd) could improve scintigraphy with radio-dThd analogues, such as 5-iodo-2'-deoxyuridine (IdUrd). We first show in vitro that coincubation with FdUrd substantially increased incorporation of [125I]IdUrd and [3H]dThd in the three tested human glioblastoma lines. Flow cytometry analysis showed that a short coincubation with FdUrd (1 h) produces a signal increase per labeled cell. We then measured biodistribution 24 h after i.v. injection of [125I]IdUrd in nude mice s.c. xenografted with the three glioblastoma lines. Compared with animals given [125I]IdUrd alone, i.v. preadministration for 1 h of 10 mg/kg FdUrd increased the uptake of [125I]IdUrd in the three tumors 4.8-6.8-fold. Compatible with previous reports, there were no side effects in mice observed for 2 months after receiving such a treatment. The tumor uptake of [125I]IdUrd was increased < or =13.6-fold when FdUrd preadministration was stepwise reduced to 1.1 mg/kg. Uptake increases remained lower (between 1.7- and 5.8-fold) in normal proliferating tissues (i.e., bone marrow, spleen, and intestine) and negligible in quiescent tissues. DNA extraction showed that 72-80% of radioactivity in tumor and intestine was bound to DNA. Scintigraphy of xenografted mice was performed at different times after i.v. injection of 3.7 MBq [125I]IdUrd. Tumor detection was significantly improved after FdUrd preadministration while still equivocal after 24 h in mice given [125I]IdUrd alone. Furthermore, background activity could be greatly reduced by p.o. administration of KClO4 in addition to potassium iodide. We conclude that FdUrd preadministration may improve positron or single photon emission tomography with cell division tracers, such as radio-IdUrd and possibly other dThd analogues. 相似文献
3.
Transferrin binding was found to be around 60-fold higher inhepatocyte nodules compared to normal liver, with no apparentdifferences in binding affinity or molecular weight of bindingproteins, indicating that the increase in [125I]trans-ferrinbinding was the result of an increased number of binding siteswith similar properties as in normal liver. The relative inductionof transferrin receptors was most marked in the total membranefraction followed by membrane sub-fractions comprising endoplasmkreticulum, the Golgi complex and endocytic vesicles. Despitethe increased number of transferrin receptors, the in vivo endocytosisof transferrin, measured as uptake of [125I]ferrotransferrin,was quantitatively similar in nodular cells compared to normalliver. The number of transferrin receptors in regenerating liver,48 h after partial hepatectomy, was increased 20-fold over normallevels, but binding affinity, receptor structure and kineticsof transferrin uptake were normal. A slower than normal rateof 59Fe accumulation in hepatocyte nodules may suggest an alterationin the dissociation of iron from ferro-transferrin, therebysuggesting one mechanism relevant to the iron storage deficiencyin nodular cells. 相似文献
4.
A I Kassis A D Van den Abbeele P Y Wen J Baranowska-Kortylewicz R A Aaronson W C DeSisto L A Lampson P M Black S J Adelstein 《Cancer research》1990,50(16):5199-5203
Glial neoplasms of the human central nervous system are malignancies that have defied treatment. Part of the problem lies in the limitations of current diagnostic techniques which are unable to identify small collections of neoplastic glia within normal parenchyma and in the difficulty of sterilizing these tumors because of limited selectivity of the cytotoxic agents available. The thymidine analogue 5-iodo-2'-deoxyuridine (IdUrd) radiolabeled with 123I and 125I was injected directly into an intracerebral rat 9L gliosarcoma and found to be a sensitive and specific agent for the detection of this neoplasm in rats. External gamma camera imaging (123I) visualized tumors as small as 0.5 mm in diameter. Autoradiography (125I) indicated that IdUrd was incorporated into the DNA of neoplastic glia only. Since 123I emits gamma-photons suitable for scintigraphy, [123I]IdUrd holds promise for the diagnosis of brain tumors in humans as well. Furthermore, since 123I and 125I are Auger electron emitters that have demonstrated antineoplastic effects, direct administration of [123I]IdUrd or [125I]IdUrd into tumors may also have potential for the treatment of central nervous system malignancies. 相似文献
5.
6.
Fujimaki T Ellis L Bucana C Radinsky R Price J Fidler I 《International journal of oncology》1993,2(6):895-901
We compared the suitability of 3 techniques to study tumor cell survival in the lungs of mice and proliferation into metastases. Genetic tagging of tumor cells with the bacterial beta-galactosidase marker gene lacZ, radiolabeling of tumor cells with [I-125]IdUrd, and S-phase labeling of cells with bromodeoxyuridine (BrdUrd) were used simultaneously to track the fate of highly metastatic K-1735 X-21 melanoma cells injected into syngeneic C3H/HeN mice. The melanoma cells were transfected with a plasmid containing lacZ and neomycin resistance genes. After growth in selective medium, the cells were incubated in medium containing [I-125]IdUrd and then injected i.v. into mice. Lungs isolated at various times after i.v. injection were processed for staining with X-gal, radioactive monitoring, and immunohistochemical staining with a monoclonal antibody against BrdUrd. At early time points, the presence of lacZ-positive cells directly correlated with radioactivity associated with viable cells. However, the expression of the beta-galactosidase was only stable for 1 week, and by 3 weeks after injection, large metastases contained only a few lacZ-positive cells. The combination of lacZ tagging with BrdUrd proliferation assay accurately identified dividing tumor cells in micrometastases. The simultaneous use of these 3 techniques allowed us to conclude that quantitative analysis of tumor cell survival is best accomplished by radioactive labeling of cells, whereas the use of lacZ-tagged cells allowed for studies of localization. Analysis of tumor cell proliferation requires the use of both lacZ tagging and immunohistochemistry using anti-BrdUrd antibodies. Since the process of metastasis consists of a series of distinct steps, each technique presents its own advantages and limitations. 相似文献
7.
F Isohashi K Tsukanaka M Terada Y Nakanishi H Fukushima Y Sakamoto 《Cancer research》1979,39(12):5132-5135
Changes in binding of dexamethasone (9 alpha-fluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione) to its receptors in regenerating rat liver after 70% hepatectomy were examined. Specific receptors for dexamethasone in the liver remnants of adrenalectomized rats decreased significantly during the period of DNA synthesis after 70% hepatectomy; then, they increased to above the control values between Days 4 and 7 after partial hepatectomy and subsequently returned to the control values. During the period of DNA synthesis, decreased binding was observed in partially hepatectomized rats with or without adrenals, but later enhanced binding was not prominent in rats with adrenals. 相似文献
8.
Topical application of benzo[a]pyrene (B[a]P) at dose rates of 32 or 64 micrograms/week to the dorsal skin of female Swiss (ICR) mice resulted in a marked and rapid increase in concentration of RNA for transforming growth factor beta 1 (TGF-beta 1) in epidermis. Two RNA species 1.9 and 2.5 kb, detected by a mouse TGF-beta 1 cDNA probe, were coordinately expressed. The concentration of these species appeared to be maximal 6-12 h after application, and returned to control levels after 48 h. A second, less intense maximum was observed 72-96 h after treatment. Similar effects were observed in CD-1 and HRS (both hr/hr and hr/+) mice, which are also sensitive to B[a[] tumorigenesis. In comparison with 32 and 64 micrograms/week a dose rate of 16 micrograms/week was essentially without activity in increasing TGF-beta 1 RNA concentration. All three dose rates induced an increase in epidermal RNA for ornithine decarboxylase, however, and with kinetics similar to those observed with the potent tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate. The results obtained support other findings made in this laboratory, that at high dose rates above 16 micrograms tumorigenesis by B[a]P involves a strong tumor-promoting component. The latter further appears to be mediated by increased TGF-beta 1 expression. 相似文献
9.
Liver regeneration studies with rat hepatocytes in primary culture 总被引:24,自引:0,他引:24
G Michalopoulos H D Cianciulli A R Novotny A D Kligerman S C Strom R L Jirtle 《Cancer research》1982,42(11):4673-4682
Adult rat parenchymal hepatocytes in primary culture can be induced to enter into DNA synthesis and mitosis. The optimal conditions for hepatocyte replication are low plating density (less than 10,000 cells/sq cm) and 50% serum from two-thirds partially hepatectomized rats (48 hr after hepatectomy). Approximately 80% of the hepatocytes enter the cell cycle, and most of these cells go through mitosis. The replicating hepatocytes remain positive for glucose-6-phosphatase and negative for gamma-glutamyl transpeptidase, and they accumulate fat, in analogy to regenerating liver. Most of the replicating hepatocytes enter into multiple consecutive rounds of DNA synthesis. Dose-response studies between control animal serum and hepatocyte labeling index indicate that in unoperated animals the serum contains substances stimulatory as well as inhibitory for hepatic growth, with the inhibitory effect prevailing at high concentrations. After partial hepatectomy, the inhibitory activity disappears whereas the hepatopoietin activity reaches almost 90% of maximal biological effectiveness at 25% serum concentration. Addition of hormones to the system shows that the hepatopoietin activity is not identical to epidermal growth factor, platelet-derived growth factor, thyroxine, glucagon, or hydrocortisone. Norepinephrine abolishes the difference between control and hepatectomized serum but does not restore hepatopoietin activity when added to heat-inactivated serum. The results show that this system of replicating hepatocytes can be used to investigate the trophic factors that control growth of normal and neoplastic hepatocytes. 相似文献
10.
Loss of transforming growth factor beta 1 (TGF-beta 1)-induced growth arrest and p34cdc2 regulation in ras-transfected epithelial cells. 总被引:2,自引:0,他引:2
Transforming growth factor beta 1 (TGF-beta 1) is a potent inhibitor of mink lung epithelial (CCL64) cell growth in culture. The fact that many transformed epithelial cells have escaped from negative growth control by TGF-beta 1 suggests that transfected epithelial cells may be an appropriate model for investigating the growth-inhibitory mechanism of TGF-beta 1. We transfected CCL64 cells with a mouse c-myc oncogene (pSVc-myc1), a mutated Harvey-ras (Ha-ras) oncogene, or a combination of both. The results indicate that cells transfected with c-myc alone exhibit normal morphology and maintain sensitivity to TGF-beta 1 growth arrest, but are unable to form colonies in soft agar in the presence or absence of TGF-beta 1. Cells transfected with Ha-ras, or co-transfected with c-myc, display a transformed morphology, grow spontaneously under anchorage-independent conditions and acquire a complete resistance to growth inhibition by TGF-beta 1. Affinity cross-linking of [125I]TGF-beta 1 to cell-surface receptors from these transfectants revealed that all three TGF-beta receptor types were present and no significant differences in [125I]TGF-beta 1 labeling of these receptors was observed. Since we have previously demonstrated that modulation of p34cdc2 kinase is a marker for TGF-beta 1 growth inhibition, we investigated p34cdc2 activity in the CCL64 transfected clones. The results show that in the control CCL64 cells and in the myc-transfected clones TGF-beta 1 regulation of p34cdc2 activity is maintained. In the ras- and ras + myc-transfected cells p34cdc2 phosphorylation and histone H1 kinase activity is significantly increased and regulation by TGF-beta 1 is lost. 相似文献
11.
Transforming growth factor receptors in liver regeneration following partial hepatectomy in the rat 总被引:6,自引:0,他引:6
Transforming growth factors alpha and beta (TGF-alpha and TGF-beta) are produced in the liver and appear to play an important role in the regulation of hepatic growth. We investigated changes in receptors for these polypeptide growth factors in regenerating liver after partial hepatectomy in the rat with comparisons to livers from normal and sham-operated animals. In normal rats, binding of 125I-epidermal growth factor (EGF) to liver membranes was fully and competitively displaced by TGF-alpha, indicating that these two growth factors share similar sites on the same hepatic receptor. Scatchard analyses revealed that EGF receptors bound EGF with 4- to 8-fold higher affinity than TGF-alpha. Following partial hepatectomy or sham operation, EGF/TGF-alpha receptor number decreased by 25, 40, and 55% at 12, 24, and 72 h, respectively. In all cases. Scatchard analysis obtained with EGF yielded a linear plot indicating a single population of binding sites with a dissociation constant (Kd) of approximately 0.9 nM. Scatchard analysis of TGF-beta binding showed that liver membranes from sham-operated and normal rats express binding sites with a Kd of approximately 35 pM. In contrast, membranes obtained from 12-, 24-, and 72-h regenerating livers were altered in a manner consistent with uncovering or appearance of a higher affinity site. Affinity labeling of liver plasma membranes with 125I-TGF-beta revealed two predominant proteins with Mr 85,000 and 66,000. In unfractionated membrane preparations, two other proteins with Mr 105,000 and approximately 150,000 were seen. Following partial hepatectomy the major change in affinity-labeled proteins was a small (10-25%) but consistent decrease in the Mr 85,000 species. These results show that receptors for TGF-alpha and TGF-beta are modulated after partial hepatectomy, a further indication that these polypeptides may have an important role in liver regeneration. 相似文献
12.
H Morimoto Y Nio S Imai T Shiraishi M Tsubono C C Tseng T Tobe 《Cancer Detection and Prevention》1992,16(2):137-147
To study the effect of hepatectomy on the growth of liver tumor, Shionogi Carcinoma 42, a mammary tumor, was transplanted into the liver of mice which had undergone 40% hepatectomy. The liver tumor and the number of pulmonary metastases in hepatectomized mice were significantly larger than those in nonhepatectomized mice. Responses to lectins and IL-2, subpopulations, and cytotoxicity to YAC-1 and P815 cells of splenocytes were assessed to evaluate immunological status. At the initial phase after hepatectomy and tumor transplantation into the remaining liver, NK activity transiently increased, and function of B and T cells, especially of helper T cells, decreased, while B-cell function recovered beyond normal levels in a later phase. These results suggest that liver may play an important immunological role and that the immunological modification after hepatectomy may be responsible for the accelerated growth of liver tumor. Accordingly, some adjuvant immunotherapy may be recommended for the prevention of recurrence after hepatectomy for liver tumor. 相似文献
13.
In vivo administration of interferon alpha and interleukin 2 induces proliferation of lymphoid cells in the organs of mice 总被引:2,自引:0,他引:2
We have previously shown that interleukin 2 (IL-2) synergizes with interferon alpha (IFN-alpha) in mediating the regression of established pulmonary and hepatic metastases and the reduction of intradermal tumor in various murine tumor models. To understand the mechanism of synergy, we have examined lymphoid cell proliferation in various organs of mice in response to IL-2 and IFN-alpha administration. We have utilized a technique for labeling newly synthesized DNA in vivo with 5-[125I]iodo-2'-deoxyuridine to examine proliferation of endogenous cells in response to IL-2 and IL-2 plus IFN-alpha. A proliferation index was calculated by dividing cpm in the tissues treated with cytokines by cpm obtained in corresponding tissues of control mice. After 4 days of IL-2 administration, a significant uptake of 5-[125I]iodo-2'-deoxyuridine was observed in the lungs, liver, kidneys, and spleen (proliferation index of 13, 10.3, 3.6, and 3.2, respectively). IFN-alpha alone mediated very little incorporation of radiolabel but when administered in combination with IL-2 a reduction of IL-2-induced proliferation was seen on day 4. For example 19,272 +/- 4,556 cpm (mean +/- SE) were obtained in the liver of IL-2-treated mice, compared to 8,103 +/- 2,111 cpm in livers of IL-2 plus IFN-alpha-treated mice (P less than 0.05). Similar inhibition of IL-2-induced proliferation was observed in the lungs, kidneys, and spleen. In contrast, on days 7 or 8, higher uptake of radiolabel was obtained in IFN-alpha plus IL-2-treated lungs, liver, and kidneys, compared to organs of mice treated with IL-2 alone or IFN-alpha alone. A proliferation index of 30.5, 9.8, and 10 was obtained in the lungs, liver, and kidneys of IL-2- plus IFN-alpha-treated animals, compared to 9.6, 3.6, and 5.5 in the corresponding organs of IL-2-treated mice. The effects of IFN-alpha on IL-2-induced proliferation was dose dependent; very low dosages of IFN-alpha (1,000 units/dose) were able to cause the inhibition of proliferation at 3 days of therapy and increase at 7 days of therapy. Continued proliferation of cells was observed in most organs when IL-2 plus IFN-alpha was injected for 9 consecutive days. Pretreatment irradiation of mice at 500 rad largely eliminated the proliferative response to IL-2 as well as to IFN-alpha plus IL-2 at both 3 and 7 days. Histological studies of lungs receiving cytokine therapy for 3 and 7 days corroborated the results of the 5-[125I]iodo-2'-deoxyuridine incorporation assay. At day 3 a significant infiltration of lymphoid cells was seen in IL-2-treated lungs, whereas little or no lymphocytic infiltration was observed in IL-2- plus IFN-alpha-treated lungs.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
14.
A monoclonal antibody (MAb) 8 [immunoglobulin G3 (IgG3)], directed against a Mr 48,000 human lung cancer-associated antigen, was radiolabeled with either 125I or 131I, and its biodistribution was studied in nude mice bearing human lung cancer (TKB-2) over a 7-day period. 125I-labeled MAb 8 increased its binding to the tumor during the period, while the binding of 125I-labeled control IgG3 declined after initial uptake. At Day 7, percentages of injected dose of 125I-labeled MAb 8 bound to the tumor rose to 7.4%, which was a 4.4-fold increase from Day 1 and 16-fold binding of 125I-labeled control IgG3 at the same day. Tumor:blood ratios became 2.7:1 at Day 7, and tumor:liver, tumor:spleen, and tumor:kidney ratios were more than 9:1. Normal organs showed no significant uptake of 125I-labeled MAb 8, compared with those of 125I-labeled control IgG3. A clear image of the xenografted tumor was obtained at Day 5, and it further improved at Day 7, when 60% of whole body radioactivity was localized to the tumor. Autoradiography of the mouse with tumor confirmed the excellent localization of 125I-labeled MAb 8 to the tumor, although the radioactivity of the tumor was not uniformly distributed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that most of the radioactivity was present at the tumor in the form of degraded immunoglobulin. MAb 8 has a potential usefulness in the diagnosis and treatment of lung cancer. 相似文献
15.
Alberto Gabizon Aviva T Horowitz Dorit Goren Dina Tzemach Hilary Shmeeda Samuel Zalipsky 《Clinical cancer research》2003,9(17):6551-6559
PURPOSE: To compare the in vivo tissue distribution of folate-targeted liposomes (FTLs) injected i.v. in mice bearing folate receptor (FR)-overexpressing tumors (mouse M109 and human KB carcinomas, and mouse J6456 lymphoma) to that of nontargeted liposomes (NTLs) of similar composition. EXPERIMENTAL DESIGN: A small fraction of a folate-polyethylene-glycol (PEG)-distearoyl-phosphatidylethanolamine conjugate was incorporated in FTLs. Both FTLs and NTLs were PEGylated with a PEG-distearoyl-phosphatidylethanolamine conjugate to prolong circulation time. Liposomes were labeled with [(3)H]cholesterol hexadecyl ether with or without doxorubicin loading. Liposome levels in plasma, tissues, or ascites were assessed by the number of [(3)H] counts. For doxorubicin-loaded formulations, we also determined the tissue doxorubicin levels by fluorimetry. To estimate the amount of liposomes directly associated with tumor cells in vivo, we determined the [(3)H]radiolabel counts in washed pellets of ascitic tumor cells using the ascitic J6456 lymphoma RESULTS: FTLs retained the folate ligand in vivo, as demonstrated by their ability to bind ex vivo to FR-expressing cells after prolonged circulation and extravasation into malignant ascitic fluid. In comparison with NTLs, FTLs were cleared faster from circulation as a result of greater liver uptake. Despite the lower plasma levels, tumor levels of FTL-injected mice were not significantly different from those of NTL-injected mice. When NTLs and FTLs were loaded with doxorubicin, liver uptake decreased because of liver blockade, and uptake by spleen and tumor increased. When tumor-to-tissue liposome uptake ratios were analyzed, the targeting profile of FTLs was characterized by higher tumor:skin, and tumor:kidney ratios but lower tumor:liver ratio than NTLs. After a concomitant dose of free folic acid, FTLs (but not NTLs) plasma clearance and liver uptake were inhibited, indicating that accelerated clearance was mediated by the folate ligand. Surprisingly tumor uptake was not significantly affected by a codose of folic acid. In the J6456 ascitic tumor model, tumor cell-associated liposome levels were significantly greater for FTL-injected mice than for NTL-injected mice, despite slightly higher levels of the latter in whole ascites. CONCLUSIONS: Whereas folate targeting does not enhance overall liposome deposition in tumors, the targeting profile of tumor versus other tissues is substantially different and intratumor liposome distribution in ascitic tumors is affected favorably with a selective shift toward liposome association with FR-expressing cells. 相似文献
16.
Reticuloendothelial system (RES) hyperfunction and erythropoietin (Ep) production in the regenerating liver 总被引:1,自引:0,他引:1
B A Naughton D J Birnbach P Liu G A Kolks M Z Tung J A Piliero S J Piliero A S Gordon 《Journal of surgical oncology》1979,12(3):227-242
Hepatic cells in rats were evaluated after subtotal hepatectomy using scintillation scanning with technetium sulfur colloid (TSC), autoradiography, and microstereology techniques. The ability of the liver to accumulate TSC increased during the course of the regeneration as did the labeling of Kupffer and parenchymal cells with tritiated thymidine (3H-tdR). Kupffer to parenchymal cell number ratios and Kupffer cell relative areas were also elevated, attaining peak values at 72 hours post-hepatectomy. This period corresponds to the time of peak erythropoietin (Ep) production in rats with regenerating livers after nephrectomy and exposure to hypoxia. These findings suggest that the Kupffer cell may function as a cellular site of Ep formation. 相似文献
17.
Transforming growth factor beta 1 induces cachexia and systemic fibrosis without an antitumor effect in nude mice 总被引:5,自引:0,他引:5
G Zugmaier S Paik G Wilding C Knabbe M Bano R Lupu B Deschauer S Simpson R B Dickson M Lippman 《Cancer research》1991,51(13):3590-3594
While stimulating the growth of fibroblasts, transforming growth factor beta 1 (TGF-beta 1) inhibits the growth of various normal and malignant cell lines in vitro. We studied the effects of TGF-beta 1 in vivo. The level of TGF-beta 1 in serum was maximally elevated 2 h after injecting 1 muCi of 125I-TGF-beta 1 into the peritoneal cavity of nude mice. Five h after the i.p. administration of 10 micrograms of unlabeled TGF-beta 1, 20 ng/ml of TGF-beta-like material in serum were detected by a radioreceptor assay on A549 lung carcinoma cells. Trichloracetic acid-precipitable 125I-TGF-beta 1 was taken up by liver, spleen, lungs, kidneys, and tumor tissue but not by the brain. At doses exceeding 2 micrograms/day, TGF-beta 1 induced a generalized interstitial fibrosis and a cachexia, which was not mediated by elevated serum levels of tumor necrosis factor alpha as determined by Western blot analysis and enzyme-linked immunosorbent assay. A total of 200,000 cells of the estrogen receptor-negative human breast cancer line MDA-MB-231, which had been shown to be maximally growth inhibited in vitro by 40 pM TGF-beta 1 and to have high-affinity receptors (9, 11, 12), were injected into the mammary fat pad of each nude mouse. The duration of treatment was 16 days with ten animals in the control group and five animals in the treated groups. The dose ranged from 1 to 4 micrograms per animal daily. The treatment was started 24 h after the injection of the tumor cells. Tumor growth was not significantly affected at either nontoxic or toxic doses of TGF-beta 1. Thus, we have demonstrated that TGF-beta 1, apart from being a local growth factor, has systemic effects, such as cachexia and multiple fibrosis. Its role as an antitumor agent may be limited. 相似文献
18.
The sensitivity to 5-fluorouracil (5-FU) and the metabolism of 5-FU in the regenerating rat liver were investigated in vitro. Determination of cell viability using the succinate dehydrogenase inhibition test showed that the hepatocytes of the partially hepatectomized liver were more sensitive to 5-FU, compared to findings in the case of normal liver. The activities of 5-FU phosphorylation of the 3 pathways were higher in the regenerating than in the intact liver and the peak increase was seen 36 h after partial hepatectomy. The activity of 5-FU degradation decreased to about 30% at 36 h and then gradually increased reaching the normal range at 72 h after partial hepatectomy. These results suggest that the metabolic changes of 5-FU may be one of the causes for increased 5-FU susceptibility in the regenerating liver. 相似文献
19.
Gibbs DD Theti DS Wood N Green M Raynaud F Valenti M Forster MD Mitchell F Bavetsias V Henderson E Jackman AL 《Cancer research》2005,65(24):11721-11728
BGC 945 is a cyclopenta[g]quinazoline-based, thymidylate synthase inhibitor specifically transported into alpha-folate receptor (alpha-FR)-overexpressing tumors. Affinity of BGC 945 for the alpha-FR is 70% of the high-affinity ligand folic acid. In contrast to conventional antifolates, BGC 945 has low affinity for the widely expressed reduced-folate carrier (RFC). The K(i) for isolated thymidylate synthase is 1.2 nmol/L and the IC(50) for inhibition of the growth of alpha-FR-negative mouse L1210 or human A431 cells is approximately 7 micromol/L. In contrast, BGC 945 is highly potent in a range of alpha-FR-overexpressing human tumor cell lines (IC(50) approximately 1-300 nmol/L). Pharmacokinetic variables measured following i.v. injection of 100 mg/kg BGC 945 to KB tumor-bearing mice showed rapid plasma clearance (0.021 L/h) and tissue distribution. The terminal half-lives in plasma, liver, kidney, spleen, and tumor were 2, 0.6, 5, 21, and 28 hours, respectively. Tumor BGC 945 concentration at 24 hours was approximately 1 nmol/g tissue, at least 10-fold higher than that in plasma or normal tissues. Inhibition of thymidylate synthase in tissues leads to increased incorporation of 5-[(125)I]-iodo-2'-deoxyuridine ([(125)I]dUrd) into DNA. Forty-eight hours after injection of 100 mg/kg 6RS-BGC 945 ([(125)I]dUrd injected at 24 hours), tumor was the only tissue with incorporation above control level (6-fold). The RFC-mediated thymidylate synthase inhibitor plevitrexed also increased uptake of [(125)I]dUrd in tumor (10-fold) but, in contrast, also caused increased incorporation in other normal tissues such as spleen and small bowel (4.5- and 4.6-fold, respectively). These data suggest that BGC 945 selectively inhibits thymidylate synthase in alpha-FR-overexpressing tumors and should cause minimal toxicity to humans at therapeutic doses. 相似文献
20.
[目的]探讨不同剂量碘[125I]粒子组织间植入对人肝癌细胞裸鼠HepG2移植瘤生长的抑制作用。[方法]构建20只人肝癌HepG2的裸鼠移植瘤模型,随机分为4组,每组5只。3个治疗组分别接受18.5MBq(A组)、29.6MBq(B组)、37MBq(C组)的碘[125I]粒子治疗,对照组(D组)不接受治疗。采用经皮肿瘤组织直接植入的方式分别将不同剂量的碘[125I]粒子植入各治疗组小鼠的瘤体内,每只小鼠瘤体内植入一粒碘[125I]粒子。观察各组小鼠的体重及瘤体体积的变化。至治疗第28d时处死所有小鼠,剥离肿瘤并称重。[结果]各治疗组小鼠瘤体的体积增长速度随碘[125I]粒子的剂量增加而逐渐降低。A、B、C组小鼠与D组小鼠的肿瘤体积相比,抑瘤率分别是41.81%、64.45%和69.69%;A、B、C组小鼠与D组小鼠的肿瘤重量相比,抑瘤率分别是31.11%、62.22%和64.44%。[结论]碘[125I]粒子组织间植入治疗可抑制荷HepG2肝癌裸鼠肿瘤的生长,抑瘤作用与剂量呈正相关。 相似文献