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1.
KN Rithidech JJ Dunn CR Gordon EP Cronkite VP Bond 《Canadian Metallurgical Quarterly》1996,22(3):271-280
N-ras mutations were examined in DNA samples extracted from the spleen of CBA/Ca mice that developed myeloid leukemia (ML) following exposure to radiations of different qualities. A total of 17 ML cases, i.e. 5 cases of neutron-induced and 12 cases of photon- (3 gamma-ray and 9 x-ray) induced ML were included in the study along with 12 DNA samples from the bone marrow cells of control mice. Polymerase chain reaction-single strand conformational polymorphisms (PCR-SSCP) and the direct sequencing of PCR products were used to analyze three regions of the N-ras gene: (i) a 120 base-pair (bp) long portion of exon I (codons 2-37); (ii) a 103 bp long portion of exon II (codons 48-82); and (iii) a 107 bp long portion of exon III (codons 118-150). PCR-SSCP mobility shifts indicated mutations within only exon II of the N-ras gene. Such mutations were more prevalent in samples from mice exposed to fast neutrons. The exact type and location of these mutations were then determined by direct DNA sequencing. Silent point mutations, i.e. base transitions at the third base of codons 57 (GAC-->GAT), 62 (CAA-->CAC), or 70 (CAG-->CAA) were present only in mice that developed ML after exposure to fast neutrons. A base transversion at the third base of codon 61 (CAA-->CAC) was also observed in some ML cases. DNA sequencing demonstrated that ML samples contained normal as well as mutated DNA sequences. The higher frequency of N-ras mutations in neutron-induced ML suggested that fast neutrons are more effective in inducing genomic instability at the N-ras region of the genome. More importantly, N-ras mutations are not the initiating event in radiation leukemogenesis. This conclusion was supported by the finding that N-ras mutations were detected only in mice with an overt leukemic phenotype but not in mice with minimal tissue infiltration of leukemic cells, suggesting that the disease may be present prior to the presence of N-ras mutations. Alternatively, N-ras may be present in these mice but a large number of normal spleen cells in these mice interferes with the detection of mutation in a small population of leukemic cells. 相似文献
2.
R Di Pietro L Centurione E Santavenere MA Centurione G Sanità Di Toppi L Zamai R Rana 《Canadian Metallurgical Quarterly》1996,10(1):253-259
A morphological study of DNA repair and apoptotic patterns in relationship with cell cycle events was performed on murine erythroleukemia cells. The presence and distribution of DNA replicon sites were evaluated through the BrdU-anti BrdU immunofluorescence and immunogold techniques in light and electron microscopy. Different patterns of labelling and percentages of BrdU positive cells were observed depending on irradiation dose (up to 60 Gy) and time in post-irradiation culture (up to 24 hours). An enlargement of the S phase of the cell cycle was evidenced 18 hours post-irradiation as determined by flow cytometry analysis. The high resolution approach showed that, in spite of several morphological alterations, BrdU labelling was present even in cells displaying early and late apoptotic features. 相似文献
3.
9-Amino-20(S)-camptothecin (9-AC) has demonstrated efficacy against several human cancer xenografts, including cancers of the colon, breast, lung, ovary, and stomach and malignant melanoma, and is currently undergoing Phase I clinical trials. In vitro data indicate that the addition of topoisomerase I inhibitors shortly after irradiation causes conversion of single-strand breaks to double-strand breaks, resulting in synergistic lethality to cultured log-phase or quiescent malignant cells. In our study, the efficacy of 9-AC as a potential radiosensitizing agent in vivo was assessed in C3Hf/Kam female mice bearing 7.6-8-mm MCa-4 mammary tumors implanted i.m. into the right posterior thigh. In one series of experiments to determine the dose dependence of 9-AC, mice were injected twice a week with either 0.5, 1.0, or 2.0 mg/kg 9-AC (total doses of 2, 4, and 8 mg/kg, respectively) either alone or 1 h before irradiation. In a second series of experiments, the schedule dependence of 9-AC was determined by giving a constant total dose of 4 mg/kg 9-AC once (2 mg/kg), twice (1 mg/kg every third day), or four (0.5 mg/kg every other day) times per week for 2 weeks, either alone or combined with radiation. The same radiation regimen was used in all experiments: 2-Gy fractions daily for 14 consecutive days, giving a total dose of 28 Gy to the tumor-bearing leg only. Tumor response was assessed by regrowth delay and dose modification factors (DMFs) obtained by comparing regrowth delay in the groups given 9-AC alone with those given the same dose of 9-AC and radiation. 9-AC significantly delayed tumor growth when combined with radiation, and this effect was dependent on drug dose; DMFs of 2.4 [95% confidence interval (CI), 2.0-3.1], 3.7 (95% CI, 3.1-4.6), and 3.3 (95% CI, 2.7-4.1) were obtained for groups treated with total drug doses of 2.0, 4.0, and 8.0 mg/kg 9-AC, respectively. In addition, the same total dose of 4 mg/kg 9-AC was more effective when given either twice or four times a week compared with once a week, giving DMFs of 2.8 (95% CI, 2.2-3.9), 2.6 (95% CI, 2.0-3.6), and 1.7 (95% CI, 1.3-2.4), respectively. The effect of 9-AC and radiation on normal tissue toxicity was assessed in two normal tissues, jejunum and skin, in separate groups of mice. Jejunal crypt cell survival was decreased in those mice given single doses of 9-AC ranging from 0.5-4.0 mg/kg and 12.5 Gy of total body radiation compared with those given 12.5 Gy of total body irradiation alone. The same regimen of drug and radiation did not modify acute skin reactions. These results suggest that 9-AC is an effective in vivo radiosensitizing agent when given in divided doses with fractionated irradiation. In addition, the gastrointestinal tract but not skin could be a critical target tissue for the use of 9-AC combined with radiation. 相似文献
4.
Pregnant Wistar-MS strain rats were irradiated with 2.6 Gy of gamma-rays at day 20 of pregnancy. Rats in the control group (n = 48) were then implanted with a diethylstilbestrol (DES) pellet at 35 days after weaning, while being fed a control (MB-1) diet. The incidence of mammary tumors was 89.6% within 1 year. In the experimental group (n = 22), a bezafibrate (0.15%) diet was initiated immediately after weaning, and 35 days after weaning a DES pellet was implanted. Administration of dietary bezafibrate together with DES-implantation continued for a period of 1 year, at which time the experiment was terminated. The incidence (27.3%) of the mammary tumors in the bezafibrate-fed rats was less than one-third of that in the control rats. Compared with the control group, the number of mammary tumors per tumor-bearing rat in the bezafibrate-treated group was reduced. For clarification of the mechanism of the chemopreventive effects of bezafibrate, lipid and hormone concentrations in serum were measured. Bezafibrate-fed rats showed a significant decrease in serum prolactin (56%) and triglyceride (63%) concentrations, and a significant increase in serum estradiol-17beta (3.8-fold), cholesterol ester (2.0-fold) and TSH (2.0-fold) concentrations in comparison with the control rats. The bezafibrate diet inhibited the formation of DES-induced pituitary tumors. However, the development of mammary glands in the bezafibrate-fed rats was stimulated more than that in the control rats treated with DES alone. The present results demonstrate that bezafibrate is effective in preventing mammary tumors induced by radiation together with DES, possibly by reducing prolactin and triglyceride concentrations. 相似文献
5.
M Peller L Weissfloch MK Stehling J Weber R Bruening R Senekowitsch-Schmidtke M Molls M Reiser 《Canadian Metallurgical Quarterly》1998,16(7):799-809
Breathing of 100% oxygen was used to challenge vascular autoregulation in 14 mice with either osteosarcomas (n = 6) or mammary carcinomas (n = 8). Reproducible and statistically significant signal intensity changes of -29 +/- 6% to +35 +/- 3% were observed on heavily T2*-weighted images in the tumors during the oxygen challenge. No significant changes were observed in muscle. For the mammary carcinomas a higher percentage of tumor voxels showed significant signal-intensity decrease (31 +/- 8%) compared to the percentage of voxels showing a signal-intensity increase (22 +/- 3%). In contrast, for the osteosarcomas, a higher percentage of tumor voxels showed signal-intensity increase (52 +/- 9%) compared to the percentage of voxels showing signal-intensity decrease (27 +/- 9%). The regional distribution of these signal intensity changes did not correlate with the signal pattern on T1-, T2-,and T2*-weighted and Gd-DTPA enhanced images acquired without breathing 100% oxygen. Most likely, the signal intensity changes represented the inability of the tumor's neovascularization for autoregulation during the oxygen challenge, particularly in hypoxic regions. Although further investigation is needed, the findings that malignant tumor tissue showed signal intensity changes, whereas normal muscle tissue did not, suggests that this technique may prove useful in distinguishing benign from malignant tissue. 相似文献
6.
The Fas antigen is a transmembrane receptor belonging to the tumor necrosis factor-alpha (TNF) receptor family that, when activated by Fas ligand or agonistic antibodies, induces death by apoptosis. Although the presence of Fas antigen in ovarian tissues has been demonstrated, little is known about whether Fas antigen is functional in the ovary. This report shows that murine granulosa cells are initially resistant to antibody-induced Fas-mediated apoptosis, but will undergo apoptosis when cotreated with TNF and interferon-gamma (IFN) or cycloheximide (CX). Granulosa cells were obtained from follicles of 23-day-old mice 2 days after injection of PMSG. Twenty-four hours after plating, cells were pretreated with either 0 or 200 U/ml IFN, which has been shown to induce Fas antigen expression and is required for Fas-mediated killing in many cell types. At 48 h, cells were treated with 2 microg/ml control IgG, 2 microg/ml anti-Fas antigen antibody (Fas mAb), 10 ng/ml TNF, or Fas mAb and TNF. Cytotoxicity (percent killing) relative to control IgG was determined at 72 h by counting granulosa cells after trypsinization. In the absence of IFN, no cytotoxicity was observed. In the presence of IFN, neither TNF or Fas mAb alone was cytotoxic, but the combination of Fas mAb and TNF resulted in 25% killing (P < 0.05). Fas antigen messenger RNA (mRNA) was detectable in cultures not treated with cytokines and was increased 5-fold by TNF, 2-fold by IFN, and 17-fold by the combination of IFN and TNF. To test whether the presence of a labile inhibitor(s) of Fas-mediated killing in granulosa cells is the cause of resistance to Fas mAb, the protein synthesis inhibitor CX was used. Experiments were performed as described above, except that cells were treated with 0.5 microg/ml CX in conjunction with other treatments at 48 h. Fas mAb treatment in the presence of CX induced 25% cell death without IFN pretreatment and 38% with IFN (P < 0.05). TNF treatment in the presence of CX had no effect alone, but potentiated the effects of Fas mAb, resulting in 56% killing in the absence of IFN and 86% killing in the presence of IFN (P < 0.05). Cells stained positively for DNA fragmentation and annexin V binding, features characteristic of apoptosis. Because initial experiments showed that treatment with TNF alone increased Fas mRNA levels, the effect of pretreating cells for 24 h with TNF before treatment with Fas mAb was tested. Pretreatment with TNF or IFN alone did not promote Fas mAb-mediated killing, but combined pretreatment with TNF and IFN resulted in 25% killing in response to Fas mAb. Treatment of cells with the combination of IFN and TNF induced a 19-fold increase in Fas antigen mRNA levels. Corresponding increases in Fas antigen protein expression on the surface of cells in response to cytokine treatments were detected by immunocytochemistry. Human TNF did not duplicate the effects of mouse TNF in inducing Fas antigen mRNA expression and Fas mAb-induced killing. As human TNF interacts exclusively with the type I, but not the type II, TNF receptor in the mouse, potentiating effects of mouse TNF on the Fas pathway are probably mediated via the type II TNF receptor. The effects of cytokine treatments on levels of mRNA for FAP-1, an inhibitor of Fas-mediated apoptosis, were determined. FAP-1 mRNA was detectable in untreated granulosa cells, and levels were not altered by treatment with TNF and/or IFN. In summary, the Fas-mediated pathway of apoptosis is functional in mouse granulosa cells that are stimulated with IFN and TNF. These cytokines may function at least partially by increasing Fas antigen expression. Granulosa cells appear to have inhibitors of the Fas antigen pathway, as treatment with CX potentiates Fas-mediated death. TNF promotes Fas-mediated killing in the presence and absence of CX. Therefore, TNF is not likely to act simply by increasing Fas antigen expression or decreasing protein inhibitors of the Fas pathway, because TNF remains effec 相似文献
7.
H Eichholtz-Wirth 《Canadian Metallurgical Quarterly》1995,72(2):287-292
Cisplatin resistance, induced in murine fibrosarcoma cells (SSK) in vitro or in vivo by low-dose irradiation, can be overcome by activation of the cyclic GMP(cGMP)-dependent transduction pathway. This is mediated either by stimulating cGMP formation with sodium nitroprusside or by replacing cGMP with a selective activator of the cGMP-dependent protein kinase, 8-bromo-cGMP. The cyclic AMP-dependent transduction pathway is not involved in cisplatin resistance. Instead, activation of cAMP sensitises both parental and resistant SSK cells equally to the action of cisplatin. There is a 1.8 to 2.5-fold increase in drug toxicity, depending on the activating agent. Enhancement of cisplatin sensitivity is induced by specific inhibition of cAMP hydrolysis, increase in cAMP formation or by increasing the activation potential to cAMP-dependent protein kinase by specific cAMP analogues. Cells that have lost cisplatin resistance respond to cGMP- or cAMP-elevating agents in the same way as the parental SSK cells. The radiation sensitivity is unchanged in all cell lines, even after activation of cAMP or cGMP. These results suggest that specific DNA repair pathways are altered by radiation but affected only in cisplatin damage repair, which is regulated by cGMP. Although there is ample cooperativity and interaction between the cAMP- and the cGMP-dependent transduction pathways, specific substrate binding by cGMP appears to play an important role in radiation-induced cisplatin resistance. 相似文献
8.
To examine the effect of stress on skin homeostasis, cutaneous barrier recovery was measured in rate exposed to immobilization stress after tape stripping or sodium dodecyl sulphate treatment. The barrier function was evaluated by measuring transepidermal water loss. Barrier recovery was delayed in rats exposed to stress in comparison with untreated controls. This tendency was observed in both male and female animals. The delay in barrier recovery was blocked by application of the sedative drugs diazepam and chlorpromazine. The barrier recovery rate in mice which were kept at a high population density (10 animals per cage) for 2 weeks was slower than that in mice kept at lower population densities (five animals or one animal per cage). These animal models could be useful for objectively quantifying the influence of stress on the cutaneous function. 相似文献
9.
WG McKenna EJ Bernhard DA Markiewicz MS Rudoltz A Maity RJ Muschel 《Canadian Metallurgical Quarterly》1996,12(2):237-245
The high-affinity receptor (R) for IL-5 consists of a unique alpha chain (IL-5R alpha) and a beta chain (beta c) that is shared with the receptors for IL-3 and granulocyte macrophage colony stimulating factor (GM-CSF). We defined two regions of IL-5R alpha for the IL-5-induced proliferative response, the expression of nuclear proto-oncogenes, and the tyrosine phosphorylation of cellular proteins including beta c, SH2/SH3-containing proteins and JAK2 kinase. In the studies described here, we demonstrate that IL-5, IL-3 or GM-CSF stimulation induces the tyrosine phosphorylation of JAK2, and to a lesser extent JAK1, and of STAT5. Mutational analysis revealed that one of the proline residues, particularly Pro352 and Pro355, in the membrane-proximal proline-rich sequence (Pro352-Pro353-X-Pro355) of the cytoplasmic domain of IL-5R alpha is required for cell proliferation, and for both JAK1 and JAK2 activation. In addition, transfectants expressing chimeric receptors which consist of the extracellular domain of IL-5R alpha and the cytoplasmic domain of beta c responded to IL-5 for proliferation and tyrosine phosphorylation of JAK1. Intriguingly, electrophoretic mobility shift assay analysis revealed that STAT5 was activated in cells showing either JAK1 or JAK2 tyrosine phosphorylation. These results indicate that activation of JAK1, JAK2 and STAT5 is critical to coupling IL-5-induced tyrosine phosphorylation and ultimately mitogenesis, and that Pro352 and Pro355 in the proline-rich sequence appear to play more essential roles in cell growth and in both JAK1/STAT5 and JAK2/STAT5 activation than Pro353 does. 相似文献
10.
Potentiation of tumour growth by carrageenan 总被引:1,自引:0,他引:1
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13.
R Tell T Heiden F Granath AL Borg S Skog R Lewensohn 《Canadian Metallurgical Quarterly》1998,77(4):643-649
Two experiments examined the frequency specificity of habituation of the acoustic startle response in the rat. Following the long-term habituation of startle to one of two pure tone stimuli in Experiment 1, animals were presented with the other stimulus. Startle response asymptotes were unaffected by this change in stimulus frequency. Short-term habituation of startle also was insensitive to stimulus frequency. In Experiment 2, pure tone stimuli were used to provoke both a startle response and the interruption of drinking. Long-term habituation of startle to either stimulus was unaffected by a change in frequency. Animals that received the two stimuli on alternating days showed as rapid a habituation as did the groups receiving only one stimulus frequency during acquisition. Conversely, the lick suppression measure was found to be frequency specific. Lick suppression durations rose to pre-habituation levels when the frequency of the stimulus was changed. Animals that received the two stimuli on alternating days showed retarded habituation compared to those groups presented with only one stimulus frequency during acquisition. Although long-term habituation of startle is not stimulus specific, it is mediated by central processes and thus remains a valuable model in the study of neurophysiological mechanisms of behavioral change. 相似文献
14.
Cytolytic antibodies to murine lymphomas elicited by immunization with allogenic and syngenic tumors
Five quaternary ammonium germicides (QAGs) were tested for their adsorption by agar. This was found to be in the following ascending order: alkylbenzylmethyl-ammonium chloride, alkyltrimethylammonium bromide, cetyltrimethylammonium bromide, cetylpyrimidinium chloride and cetylbenzyldimethylammonium chloride. An inverse relationship was established between the extent of agar binding of the QAGs and their inhibition zones. In an attempt to develop a sensitive cup-plate assaying technique suitable for QAGs, important factors affecting the agar-diffusion of QAGs were investigated. These included the influence of various polysorbates, buffer ions, agars and test organisms. Furthermore, the effect of the pH and/or the concentration of the selected polysorbate and the buffer were studied. The best medium developed for the sensitive agar-diffusion assay of QAGs was nutrient agar-Tris (0.05 M, pH 8) provided that distilled water and polysorbate 20 (0.5%) were used as diluents for the mixed alkyl and the pure cetyl QAGs, respectively. 相似文献
15.
Flow microfluorometry has been used to characterize the effects of serum concentration and cell density on the initiation of cell cycle transit of stationary phase (G0) human diploid fibroblasts (strain WI-38). The concentration of serum used to stimulate these cultures had no effect on the time cells began appearing in S (the DNA synthetic period), nor on the synchrony with which they moved around the cell cycle. However, as the serum concentration increased, the fraction of the stationary phase population released from G0 increased. Cell density modulated the ability of serum to stimulate cell cycle traverse. For example, at a cell density of 1.81 X 10(4) cells/cm2, 78% of the population was sensitive to serum stimulation; whereas, when the density was increased to 7.25 X 10(4) cells/cm2, only 27% of the population could be stimulated. This effect of cell density on the serum response is not simply the result of changing the ratio of serum concentration to cell density, but appears to reflect a true modulation of the population's sensitivity to serum stimulation. These results are consistent with the interpretation that the primary action of serum is to determine the transition of cells from a non-cycling G0 state to a cycling state and that cell density determines the proportion of the population capable of undergoing this transition. 相似文献
16.
IH Ayhan 《Canadian Metallurgical Quarterly》1976,223(2):282-286
A retrospective study of sixteen patients with pelvic fractures compounded through the perineum, rectum, or vagina showed a mortality of 50 per cent. The cause of death in seven of the eight patients was sepsis and multisystem failure. The initial surgical management of these patients must include complete diversion of the fecal stream so that pelvic and systemic sepsis may be prevented. 相似文献
17.
NL Weintraub X Fang TL Kaduce M VanRollins P Chatterjee AA Spector 《Canadian Metallurgical Quarterly》1997,81(2):258-267
Epoxyeicosatrienoic acids (EETs) are potent endothelium-derived vasodilators formed from cytochrome P-450 metabolism of arachidonic acid. EETs and their diol products (DHETs) are also avidly taken up by endothelial cells and incorporated into phospholipids that participate in signal transduction. To investigate the possible functional significance of EET and DHET incorporation into cell lipids, we examined the capacity of EETs and DHETs to relax porcine coronary arterial rings and determined responses to bradykinin (which potently activates endothelial phospholipases) before and after incubating the rings with these eicosanoids. 14,15-EET and 11,12-EET (5 mumol/L) produced 75 +/- 9% and 52 +/- 4% relaxation, respectively, of U46619-contracted rings, whereas 8,9-EET and 5,6-EET did not produce significant relaxation. The corresponding DHET regioisomers produced comparable relaxation responses. Preincubation with 14,15-EET, 11,12-EET, 14,15-DHET, and 11,12-DHET augmented the magnitude and duration of bradykinin-induced relaxation, whereas endothelium-independent relaxations to aprikalim and sodium nitroprusside were not potentiated. Pretreatment with 2 mumol/L triacsin C (an inhibitor of acyl coenzyme A synthases) inhibited [3H]14,15-EET incorporation into endothelial phospholipids and blocked 11,12-EET- and 14,15-DHET-induced potentiation of relaxation to bradykinin. Exposure of [3H]14,15-EET-labeled endothelial cells to the Ca2+ ionophore A23187 (2 mumol/L) resulted in a 4-fold increased release of EET and DHET into the medium. We conclude that incorporation of EETs and DHETs into cell lipids results in potentiation of bradykinin-induced relaxation in porcine coronary arteries, providing the first evidence that incorporated EETs and DHETs are capable of modulating vascular function. 相似文献
18.
F Goldwasser M Valenti R Torres KW Kohn Y Pommier 《Canadian Metallurgical Quarterly》1996,2(4):687-693
Camptothecin (CPT) derivatives are presently in ongoing Phase I/II clinical trials. The interactions between 9-aminocamptothecin (9AC) and cisplatin (CDDP) have been studied in the IGROV-1 human ovarian cancer cell line used in the National Cancer Institute Drug Discovery Anticancer Screen. One-h simultaneous treatment with 9AC and CDDP produced synergistic cytotoxicity. Under these conditions, 9AC delayed the reversal of CDDP-induced DNA interstrand cross-links (ISCs) without modifying the maximum ISC frequency at 6 h after drug treatment. CDDP did not affect the amount and the kinetics of reversion of 9AC-induced DNA single-strand breaks. Simultaneous treatment with CDDP and 9AC prolonged the DNA synthesis inhibition produced by each drug alone. Consistently, flow cytometry analyses showed enhanced S-phase arrest in cells treated with the CDDP-9AC combination. The DNA polymerase inhibitor aphidicolin also increased the residual CDDP-induced ISCs. These results suggest that prolonged inhibition of DNA synthesis by CPTs potentiate the cytotoxicity of CDDP by inhibiting the reversal of CDDP-induced DNA damage. Therefore, the combination of CPTs and CDDP appears to be worthwhile in cancer chemotherapy. 相似文献
19.
Net accumulation of methotrexate by carrier-mediated transport in different murine tumor cells in vitro exhibits a positive correlation with the relative drug pharmacokinetics and therapeutic responsiveness in these tumors in vivo. The transport of methotrexate by Sarcoma 180, Ehrlich carcinoma, P388, P288, and L1210 leukemia cells is qualitatively similar. Influx of drug exhibits saturation kinetics and is highly temperature dependent (Q10, 6.1 to 9.4). Efflux of exchangeable methotrexate from all of the different tumor cells exhibited first-order kinetics and the same high temperature dependence seen for influx (Q10, 6.1 to 8.0). The major kinetic determinant of responsiveness is the Km for influx. Values vary from 3.1 to 11.2 X 10(-6) M and are highest in cells from a nonresponsive Sarcoma 180 tumor, somewhat lower in the poorly responsive Ehrlich tumor, lower in moderately responsive P388 and P288 leukemias, and lowest in the highly responsive L1210 leukemia. Values for the influx Vmax differ to some extent, but in a manner not correlatable with responsiveness. The level of responsiveness of the P388 leukemia in vivo can also be partially attributed to an efflux rate that is lower than that measured for the other tumor cells. Steady-state levels of drug accumulation in vitro reflected influx and efflux rates and were consistently correlatable with therapeutic responsiveness. There was no significant difference in the extent to which folate and reduced 5-substituted folate derivatives compete with methotrexate for uptake in cells from all five tumors. The average value for Ki measured with folate for each tumor cell type was 50- and 80-fold higher than for 5-formyltetrahydrofolate and 5-methyltetrahydrofolate. 相似文献
20.
BW Light WD Yu MC McElwain DM Russell DL Trump CS Johnson 《Canadian Metallurgical Quarterly》1997,57(17):3759-3764
In a murine squamous cell carcinoma (SCC) model, we have demonstrated that both 1,25-dihydroxycholecalciferol (1,25-D3) and the analogue 1,25-dihydroxy-16-ene-23-yne-cholecalciferol (Ro23-7553) have significant in vitro and in vivo antitumor activity. We have examined here the cell cycle effect of 1,25-D3 and Ro23-7553 on SCCVII/SF tumor cells by quantitating nuclear DNA using a detergent-trypsin method via flow cytometry analysis. Both 1,25-D3 and Ro23-7553 resulted in a significant increase of cells in G0-G1, with an accompanying decrease of cells in S phase. The ability to arrest cells in G0-G1 has been exploited by combining Ro23-7553 with the cytotoxic agent cisplatin (cis-diamminodichloroplatinum; cDDP). Using the in vitro clonogenic assay, pretreatment with Ro23-7553 for 24-48 h significantly enhanced cDDP-mediated tumor cell kill as compared to concurrent treatment with Ro23-7553 and cDDP or cDDP alone. To examine the effect of Ro23-7553 and cDDP in vivo, C3H/HeJ mice with 9-14-day SCC tumors were treated either for 3 days with varying i.p. doses of Ro23-7553 or for 7 days continuously through the use of Alzet pumps, and on the last day of Ro23-7553 treatment, cDDP (1-6 mg/kg) was administered. Using the in vivo excision tumor cell clonogenic assay, in which tumors were removed from animals 24 h after cDDP treatment and plated in a clonogenic assay, pretreatment with Ro23-7553 markedly enhanced cDDP-mediated clonogenic tumor cell kill, even at low doses of cDDP as compared to cDDP treatment alone. Similarly, a significant decrease in fractional tumor volume and increase in tumor regrowth delay was observed when animals were pretreated before cDDP with Ro23-7553 as compared to either agent alone. These results demonstrate a significant enhanced antitumor effect with Ro23-7553 pretreatment before cDDP both in vitro and in vivo and suggest that Ro23-7553 may potentiate cDDP cytotoxicity through effects on cell cycle progression. 相似文献