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Biomedical subjects

G Scambia

Publications and source records attributed to G Scambia.

At least 55 records · Page 3Linked to original sources
PubMed2002

Administration of low-dose interleukin-2 plus G-CSF/EPO early after autologous PBSC transplantation: effects on immune recovery and NK activity in a prospective study in women with breast and ovarian cancer.

This study evaluated the effects of low-dose IL-2 plus G-CSF/EPO on post-PBSC transplantation (PBSCT) immune-hematopoietic reconstitution and NK activity in patients with breast (BrCa) and ovarian cancer (OvCa). To this end, two consecutive series of patients were prospectively assigned to distinct post-PBSCT cytokine regimens (from day +1 to day +12) which consisted of G-CSF (5 microg/kg/day) plus EPO (150 IU/kg/every other day) in 17 patients (13 BrCa and 4 OvCa) or G-CSF/EPO plus IL-2 (2 x 10(5) IU/m(2)/day) in 15 patients (10 BrCa and 5 OvCa). Hematopoietic recovery and post-transplantation clinical courses were comparable in G-CSF/EPO- and in G-CSF/EPO plus IL-2-treated patients, without significant side-effects attributable to IL-2 administration. In the early and late post-transplant period a significantly higher PMN count was observed in G-CSF/EPO plus IL-2-treated patients (P = 0.034 and P = 0.040 on day +20 and +100, respectively). No significant differences were found between the two groups of patients in the kinetics of most lymphocyte subsets except naive CD45RA(+) T cells which had a delayed recovery in G-CSF/EPO plus IL-2 patients (P = 0.021 on day +100). No significant difference was observed between NK activity in the two different groups, albeit a significantly higher NK count was observed in G-CSF/EPO plus IL-2 series on day +20 (P = 0.020). These results demonstrate that low-dose IL-2 can be safely administered in combination with G-CSF/EPO early after PBSCT and that it exerts favorable effects on post-PBSCT myeloid reconstitution, but not on immune recovery.

Adult↗
PubMed2002

Transforming growth factor-beta1 transcriptionally activates CD34 and prevents induced differentiation of TF-1 cells in the absence of any cell-cycle effects.

A number of cytokines modulate self-renewal and differentiation of hematopoietic elements. Among these is transforming growth factor beta1 (TGF-beta1), which regulates cell cycle and differentiation of hematopoietic cells, but has pleiotropic activities depending on the state of responsiveness of the target cells. It has been previously shown by us and other authors that TGF-beta1 maintains human CD34(+) hematopoietic progenitors in an undifferentiated state, independently of any cell cycle effects, and that depletion of TGF-beta1 triggers differentiation accompanied by a decrease in CD34 antigen expression. In the present work, we show that exogenous TGF-beta1 upregulates the human CD34 antigen in the CD34(+) cell lines TF-1 and KG-1a, but not in the more differentiated CD34(-) cell lines HL-60 and K-562. We further studied this effect in the pluripotent erythroleukemia cell line TF-1. Here, TGF-beta1 did not effect cell growth, but induced transcriptional activation of full-length CD34 and prevented differentiation induced by differentiating agents. This effect was associated with nuclear translocation of Smad-2, activation of TAK-1, and with a dramatic decrease in p38 phosphorylation. In other systems TGF-beta1 has been shown to activate a TGF-beta-activated kinase 1 (TAK1), which in turn, activates p38. The specific inhibitor of p38 phosphorylation, SB202190, also increased CD34 RNA expression, indicating the existence of a link between p-38 inhibition by TGF-beta1 and CD34 overexpression. Our data demonstrate that TGF-beta1 transcriptionally activates CD34 and prevents differentiation of TF-1 cells by acting independently through the Smad, TAK1 and p38 pathways, and thus provide important clues for the understanding of hematopoietic development and a potential tool to modify response of hematopoietic cells to mitogens or differentiating agents.

Antigens, CD34↗
PubMed2002

Detection of central pelvic recurrent disease with transvaginal color Doppler ultrasound in women treated for gynecological malignancy.

OBJECTIVE: To evaluate color Doppler characteristics of small recurrent tumors detected within the central pelvis in follow-up patients treated for gynecological malignancy. PATIENTS AND METHODS: A prospective study was performed on 340 patients who were being monitored following treatment for gynecological malignancies. A selected group of 27 patients, with small pelvic masses located in the central region of the pelvis, underwent a color Doppler examination. A subjective assessment of the vascularization (vascular score), the lowest resistance index (RI), the highest peak velocity (PSV) and the highest time averaged maximum velocity (TAMXV) of the vessels detected within the lesion were analyzed. RESULTS: In 16 patients the pelvic mass was found to be benign while in 11 patients a malignant recurrence was diagnosed. Gray-scale examination could not differentiate between benign and malignant lesions. The color score of tumor recurrences was significantly higher in comparison to that in benign lesions (color score 3 in 54% vs. 0%, P < 0.005). The malignant lesions showed significantly lower mean values of RI and significantly higher mean values of PSV and TAMXV when compared with benign lesions (0.39 +/- 0.09 vs. 0.81 +/- 0.22, P < 0.0001; 19.3 +/- 4.7 vs. 10.5 +/- 5.6 cm/s, P < 0.0001; 8.9 +/- 3.7 vs. 4.3 +/- 2.7 cm/s, P < 0.005). CONCLUSIONS: Color Doppler analysis added to transvaginal gray-scale ultrasonography seems to be a helpful tool in the diagnosis of recurrent tumors in the central region of the pelvis.

Adult↗
PubMed2002

Increased cyclooxygenase-2 (COX-2) expression is associated with chemotherapy resistance and outcome in ovarian cancer patients.

BACKGROUND: Cyclooxygenase-2 (COX-2) expression is associated with aggressive clinicopathological parameters and unfavourable prognosis in several human malignancies. The aim of this study was to investigate the expression of COX-2 and its association with clinicopathological parameters, response to treatment, and clinical outcome in ovarian cancer patients. PATIENTS AND METHODS: COX-2 expression was analysed by immunohistochemistry in 87 primary ovarian carcinomas from patients with measurable disease after primary laparotomy. RESULTS: COX-2 immunoreaction was observed in 39 (44.8%) cases, and did not differ in distribution according to age, FIGO stage, debulking at time of surgery, presence of ascites, histotype or tumour grade. Both in patients cytoreduced at first surgery and in those undergoing only explorative laparotomy, the percentage of COX-2 positivity was significantly higher in non-responding than in patients responding to treatment (P = 0.043 and P = 0.0018, respectively). In multivariate analysis, only COX-2 positivity and older age retained an independent role in predicting a poor chance of response to treatment. There was no significant difference of clinical outcome according to COX-2 status in patients undergoing primary debulking while, in the subgroup of patients who underwent explorative laparotomy, COX-2-positive cases showed a shorter time to progression (P = 0.025) and overall survival (P = 0.025). CONCLUSIONS: The assessment of COX-2 status could provide additional information in order to identify ovarian cancer patients with a poor chance of response to chemotherapy and potentially candidates for more individualised treatments.

Adult↗
PubMed2002

The role of hematopoietic stem cells in the treatment of ovarian cancer.

In recent years hematopoietic stem cells (HSC) have been the object of new research efforts and scientific advances. Therapeutic strategies have been set up using HSC for the treatment of solid tumors such as ovarian cancer. In this context different approaches have been proposed and clinically investigated. The "autologous" approach refers to the use of HSC as hematologic support to high-dose chemotherapy regimens, and to the use of HSC as an abundant source of dendritic cells for cancer vaccination protocols. Our institution has developed a long-term experience in high-dose chemotherapy with autologous HSC transplantation as first-line treatment of advanced ovarian cancer, and in the use of cytokines both for the HSC collection and for the post-transplantation hematopoietic recovery. Moreover, the "allogeneic" approach with HSC consists of the allogeneic transplantation with both myeloablative/standard or nonmyeloablative/reduced conditioning regimens, which has been proposed as a new adoptive immunotherapeutic treatment for different nonhematologic malignancies. Perspectives in the use of HSC in oncology comprise the possibility of an HSC ex vivo expansion, the use of umbilical cord blood HSC, and the development of future HSC-based gene-therapy programs.

Animals↗
PubMed2001

Systematic pelvic and aortic lymphadenectomy in elderly gynecologic oncologic patients.

BACKGROUND: Retroperitoneal lymph node dissection is a fundamental step in the surgical management of patients with pelvic gynecologic malignancies, but its applicability to geriatric patients is controversial. The objective of this study was to evaluate whether pelvic and aortic lymphadenectomy in elderly patients with gynecologic malignancies can be a safe procedure in terms of morbidity and mortality. METHODS: In a retrospective case-control study, the authors compared morbidity, mortality, and surgical data in a series of elderly patients (age > 70 years) with endometrial and ovarian carcinoma who underwent surgery. Patients were divided into two groups: Cases were 36 elderly patients who underwent surgery and pelvic and/or aortic lymphadenectomy and were matched with 72 controls, who were patients who underwent surgery without lymphadenectomy. RESULTS: Cases showed a significantly longer median operative time than controls (median, 162 minutes [range, 85-330 minutes] vs. median, 100 minutes [range 20-310 minutes], respectively; P = 0.003). No significant difference between the two groups in terms of blood loss, blood transfusions, intraoperative complications, duration of ileus, reintervention required, or postoperative hospital stay were observed. One patient in the control group died. The type and frequency of severe postoperative complications in the two groups were not substantially different. CONCLUSIONS: Pelvic and aortic lymphadenectomy was performed safely in elderly patients age > or = 70 years with endometrial and ovarian carcinoma without an increase in morbidity and mortality. Advanced chronologic age alone should not be considered a contraindication to full surgical treatment in these patients.

Age Factors↗
PubMed2001

Quercetin abrogates taxol-mediated signaling by inhibiting multiple kinases.

Cell cycle block in G(2)/M initiates apoptosis, but the mechanism of this signaling cascade are largely unknown. The microtubule-perturbing agent Taxol has multiple effects on this signaling pathway and is a potent inducer of apoptosis. The specific pathways activated by low, clinically relevant concentrations of the drug are still largely unknown and are dependent on cell type and drug concentration. In this work, we have investigated why HeLa cells respond to Taxol by undergoing complete apoptosis, whereas MCF-7 cells remain in an intermediate phase with reduced death. Three phases were distinguished in these apoptotic pathways. The initial phase characterized by cellular detachment is followed by a second phase which includes the onset of apoptotic morphology, and p38 and Bcl-2 phosphorylation. These two phases are common to both cell lines. HeLa cells then proceed to the third and final execution phase, which culminates in death, whereas MCF-7 cells do not progress. Interestingly, the isoflavonoid Quercetin, a known general kinase inhibitor and an antioxidant, was able to prevent the onset of Taxol-induced cellular detachment and to protect from cell death. Moreover, it blocked Taxol-induced phosphorylation of p38 and Bcl-2, and prevented a Taxol-induced change in relative mobility of the apoptosis signal-regulating kinase 1 (Ask1). Our data elucidate the signaling pathways activated by Taxol at low clinically relevant concentrations.

Antioxidants↗
PubMed2001

Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells.

BACKGROUND: Defects in the cell cycle machinery of prostate cancer cells might impair the efficiency of cell cycle checkpoints and affect the cell response to chemotherapeutic drugs. We examined the relationship between the status of microtubule damage-activated checkpoints and the response of hormone-refractory prostate cancer cells to paclitaxel. METHODS: The two cell lines DU145 and PC3 harboring defects at proteins involved in the regulation of checkpoints activated by microtubule damage were examined for cell sensitivity, apoptotic response, and efficiency of checkpoints in response to paclitaxel. RESULTS: In spite of a comparable sensitivity to the antiproliferative effects of paclitaxel, DU145 and PC3 cells exhibited different cell cycle control at checkpoints activated by microtubule damage. A transient mitotic arrest was induced by the taxane in both cell lines. However, PC3 cells underwent a rapid mitotic slippage and displayed a defective postmitotic checkpoint as evidenced by the appearance of polyploid cells. In this cell line, paclitaxel-induced cell death was a slow and delayed event, occurring also after S-phase re-entry. The mitotic checkpoint appeared to be more stringent in DU145 cells compared to PC3 cells. Moreover, despite the expression of mutated proteins involved in the prevention of DNA endoreduplication (p53, pRb, and p16(INK4A)), these cells did not progress into the cell cycle but efficiently underwent apoptosis by 24 hr. Such a response of DU145 cells was associated with phosphorylation of the p21(WAF1) protein. CONCLUSIONS: These observations evidence that activation of checkpoints following microtubule damage in prostate cancer may be regulated through complex mechanisms possibly involving p21(WAF1). Our findings support that the status of cell cycle checkpoints might affect the modality of cell death. However, the relevance of the mode of cell death for the sensitivity to taxanes remains to be determined.

Antineoplastic Agents, Phytogenic↗
PubMed2001

GLUT-1 expression in ovarian carcinoma: association with survival and response to chemotherapy.

BACKGROUND: Cancer cell growth is an energy-related process supported by an increased glucose metabolism. The objective of this study was to investigate the association of GLUT-1 with response to chemotherapy and outcome in patients with ovarian carcinoma. METHODS: Histologic sections of formalin fixed, paraffin embedded specimens from 113 primary ovarian carcinomas were stained for GLUT-1 by using polyclonal GLUT-1 antibody (Dako Co., Carpinteria, CA) and the labeled streptavidin biotin procedure. Intensity of GLUT-1 staining was compared with disease free survival (DFS), chemotherapy response, and other clinicopathologic characteristics. RESULTS: GLUT-1 cytoplasmic membrane staining was observed in 89 of 104 (85.6%) malignant tumors. Poorly differentiated tumors showed a trend to overexpress the GLUT-1 protein compared with the more differentiated counterparts (27.6% vs. 8.7%; P = 0.08). Patients who experienced a complete clinical response to chemotherapy were more frequently GLUT-1 positive than GLUT-1 negative (80% vs. 51.5%; P = 0.036). In multivariate analysis of advanced stage disease, residual tumor (P = 0.0001) and high GLUT-1 expression levels (P = 0.028) were the only independent variables that maintained a significant association with response to chemotherapy (P = 0.0001; chi-square = 38.13). In the subgroup of Stage III-IV (International Federation of Gynecology and Obstetrics patients showing a complete clinical response, GLUT-1 overexpression was associated with a shorter DFS. The median time to progression was 30 months in GLUT-1 strongly positive cases (> 50% of cancer cells positive) versus 60 months in GLUT-1 weakly positive cases (< or = 50% of cancer cells positive; P = 0.024). CONCLUSIONS: GLUT-1 status is an independent prognostic factor of response to chemotherapy in advanced stage ovarian carcinoma. Moreover, patients overexpressing GLUT-1 show a significantly shorter DFS. These results suggest that the assessment of GLUT-1 status may provide clinically useful prognostic information in patients with ovarian carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Microsatellite instability is an independent indicator of recurrence in sporadic stage I-II endometrial adenocarcinoma.

PURPOSE: The aim of this study was to define the prognostic role of microsatellite status in 65 stage I-II primary sporadic endometrioid endometrial adenocarcinoma (EEA) patients. PATIENTS AND METHODS: Familiarity for neoplasia was ascertained in all patients on the basis of a questionnaire. Microsatellite status was assessed by matching normal and tumoral DNA probed for five dinucleotide repeats and one mononucleotide repeat marker. Microsatellite status was analyzed in relation to clinicopathologic characteristics of the patients and length of disease-free survival (DFS). RESULTS: Eleven tumors (17%) of 65 had instability at two or more loci and were considered as unstable or microsatellite instability (MI). Tumors with no instability or instability at one locus were classified as microsatellite stable (MS). The percentage of MI was significantly higher in poorly than in well to moderately differentiated tumors (50% v 9%; P =.003). The 5-year DFS rate of MI patients was 63% (95% confidence interval [CI], 35% to 91%) versus 96% (95% CI, 91% to 101%) of MS patients (P =.0004). In multivariate analysis, only the presence of MI, stage II of disease, and depth of myometrial invasion greater than 50% retained independent prognostic roles. CONCLUSION: The assessment of microsatellite status may provide useful information for preoperative prognostic characterization of stage I-II primary sporadic EEA patients in which more individualized treatment options can be attempted.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Is there a place for a less extensive radical surgery in locally advanced cervical cancer patients?

OBJECTIVE: The aim of this study was to assess the association among the pathological status of different lymph node groups and parametrium in a single institutional population of 103 locally advanced cervical cancer (LACC) cases who underwent surgery after a neoadjuvant approach. A series of 29 early cervical cancer patients was also included in the analysis. METHODS: Eighty-two LACC patients with documented clinical response to neoadjuvant treatment and 29 early stage cases underwent radical surgery. The operative technique consisted of a type II-V radical hysterectomy and systematic pelvic lymphadenectomy (median number of lymph nodes removed 46; range 5-140). Sixty-four cases were submitted to para-aortic lymphadenectomy up to the level of the inferior mesenteric artery (median number of lymph nodes removed 13; range 1-37). RESULTS: Two subgroups of lymph nodes were defined: lower pelvic lymph nodes (LPN), including obturator and external iliac nodes, and upper pelvic nodes (UPN) including common iliac, presacral, and internal iliac nodes. Metastatic UPN involvement showed a strict association with LPN involvement: in LACC cases, 6 of 7 (86%) positive UPN cases had tumor disease at the LPN level. The single positive UPN case with negative LPN was intraoperatively identified by palpation and frozen section. Similarly, in early cervical cancer patients, 100% of positive UPN cases showed metastatic involvement at the LPN level. Sixty-three of 70 (90%) LACC patients with negative histological parametrium had negative LPN. Among 12 cases with metastatic involvement of parametrium, 5 cases (41.7%) had positive LPN. In early stage cervical cancer, 23 of 27 (85%) cases with negative parametrium showed no lymph nodal involvement. Intraoperative palpation of the parametrium could identify all cases with parametrial involvement not predicted by LPN status. CONCLUSIONS: These data offer the basis for tailoring the extent of radical surgery in LACC patients, through the selection of those lymph node stations likely to provide reliable information on the pathological status of UPN and parametrium.

Adult↗
PubMed2001

Effects of granulocyte-colony-stimulating factor and granulocyte/macrophage-colony-stimulating factor administration on T cell proliferation and phagocyte cell-surface molecules during hematopoietic reconstitution after autologous peripheral blood progenitor cell transplantation.

Thirty-four ovarian and breast cancer patients received autologous peripheral blood progenitor cell transplantation after high-dose myeloablative chemotherapy and either granulocyte-colony-stimulating factor (G-CSF) or granulocyte/macrophage-colony-stimulating fictor (GM-CSF) in the immediate post-transplant period. The recovery of T cell functionality was monitored by a three-color flow-cytometric approach using carboxyfluorescein diacetate succinimidyl ester, a probe the fluorescence intensity of which halves at each round of cell replication, in conjunction with CD3 and CD25 monoclonal antibodies. There was no significant difference between the two treatments on days 12, 20, and 40, T cell proliferation always being considerably lower than that of control cultures from healthy donors. At day 80, a significantly higher proportion of mitogen-stimulated T cells from GM-CSF-treated patients expressed interleukin-2 receptor, and a higher proportion of these T cells were actively proliferating. This phenomenon did not reflect any difference in the relative proportion of various lymphocyte subsets (T cells, CD4 and CD8+ T cells, CD45RA+ and CD45RO- T cells, and natural killer cells). At the end of follow-up (1-1.5 years) T cell proliferation had returned to values typically observed in healthy individuals in both groups of patients. Soon after transplantation (day 12), neutrophils from G-CSF-treated patients had a more elevated Fcgamma receptor I density and monocytes from GM-CSF-treated patients had a more elevated Fcgamma receptor II and MHC class II molecules density. The up-modulation of Fcgamma receptor II was maintained until day 40. Thus, administering G-CSF and GM-CSF in the post-transplant period affects T lymphocyte proliferation and phagocyte membrane molecules differently.

Adult↗
PubMed2001

A multicentre collaborative study on the use of cold scalpel and electrocautery for midline abdominal incision.

BACKGROUND: Although studies in animals demonstrated a better wound healing after abdominal incision with cold scalpel than with electrocautery, clinical experiences did not confirm these findings. The purpose of this study was to compare early and late wound complications between diathermy and scalpel in gynecologic oncologic patients undergoing midline abdominal incision. METHODS: Patients undergoing midline abdominal incision for uterine malignancies were divided into two groups according to the method used to perform the abdominal midline incision: cold scalpel and diathermy in coagulation mode. Early and late complications were compared. Logistic regressions were used for statistical analysis. RESULTS: Nine hundred sixty-four patients were included, of whom 531 were in the scalpel group and 433 in the electrocautery group. Both groups were similar with respect to demographic, operative, and postoperative characteristics. Univariate analysis revealed a higher incidence of severe wound complications in the scalpel group than in the electrocautery group (8 of 531 versus 1 of 433, P <0.05). After adjustment for confounding variables (eg, age, body mass index) no differences were found between groups. CONCLUSIONS: Scalpel and diathermy are similar in terms of early and late wound complications when used to perform midline abdominal incisions. Therefore the choice of which method to use remains only a matter of surgeon preference.

Cross-Sectional Studies↗
PubMed2001

T-cell apoptosis induced by granulocyte colony-stimulating factor is associated with retinoblastoma protein phosphorylation and reduced expression of cyclin-dependent kinase inhibitors.

Peripheral blood progenitor cells (PBPC) mobilized by granulocyte colony-stimulating factor (G-CSF) promptly engraft allogeneic recipients after myeloablative chemotherapy for hematologic malignancies. Surprisingly, no exacerbation of acute graft-vs-host disease has been observed despite a 10-fold higher T-cell content in PBPC compared with bone marrow allografts. Because G-CSF can suppress T-cell proliferation in response to mitogens and enhance their activation-induced apoptosis, we examined the molecular mechanisms underlying G-CSF-induced immune dysfunction. Normal allogeneic lymphocytes were challenged with phytohemagglutinin in the presence of serum collected after G-CSF administration (postG) to healthy PBPC donors, and the expression of key components of the cell cycle and apoptotic machineries was investigated by flow cytometry and Western blotting. Lymphocyte stimulation was associated with collapse of mitochondrial transmembrane potential, hypergeneration of reactive oxygen intermediates, and activation of caspase-3 and DNA fragmentation. Lymphocytes were arrested in a G(1)-like phase of the cell cycle, as measured by G(1)-phase cyclin expression and bromodeoxyuridine (BrdUrd) incorporation. Cell tracking experiments confirmed the occurrence of a lower number of population doublings in postG compared with preG cultures. Unexpectedly, the phosphorylation state of the protein encoded by the retinoblastoma susceptibility gene (pRB) was unaltered in postG cultures, and the inhibition of cell cycle progression occurred without the recruitment of the cyclin-dependent kinase inhibitors p15(INK4B), p16(INK4A), and p27(Kip1). We eventually evaluated the ability of antioxidant/cytoprotectant agents to prevent the G-CSF-induced mitochondrial dysfunction and inhibition of cell cycle progression. Of interest, both N-acetylcysteine and amifostine reduced apoptotic cell death by 45% on average, inhibited the activation/processing of caspase-3, and increased BrdUrd incorporation in postG cultures. Based on these experimental findings, a model is proposed in which T-cell activation in the presence of serum immunoregulatory factor(s) induced by G-CSF is associated with a molecular phenotype mimicking the G(1)-S transition and consisting of pRB phosphorylation, lack of CDKI recruitment, and reduced cyclin-E expression. The putative relationship between lymphocyte mitogenic unresponsiveness and apoptosis induction would occur at the level of key molecules shared by the cell cycle and apoptotic machineries. Whether the G-CSF-mediated modulation of lymphocyte functions in vitro is beneficial in transplantation medicine remains to be determined.

Acetylcysteine↗
PubMed2001

Immune reconstitution after autologous peripheral blood progenitor cell transplantation: effect of interleukin-15 on T-cell survival and effector functions.

OBJECTIVE: The aim of this study was to evaluate the occurrence of T-cell spontaneous apoptosis (A(spont)) and its modulation in vitro by the interleukin-2 receptor (IL-2R) gamma-chain (gammac)-signaling cytokine IL-15 in patients transplanted with autologous peripheral blood progenitor cells (PBPC) for hematologic malignancies. MATERIALS AND METHODS: Patients were examined on days 30-60, 60-90, and 90-120 after PBPC infusion. Dissipation of mitochondrial transmembrane potential, a hallmark of T-cell apoptosis, has been detected using the fluorescent probe 3,3'-dihexyloxacarbocyanine iodide, after short-term T-cell culture in the absence or presence of exogenous cytokines. Expression of Bcl-2 family members has been studied by flow cytometry and reverse transcriptase polymerase chain reaction. T-cell proliferative responses to recall antigens have been estimated in autologous mixed leukocyte cultures. RESULTS: A(spont) was seen in 45% +/- 6% of CD4(+) and 55% +/- 6% of CD8(+) T cells cultured in the absence of cytokines. Of interest, IL-15 and, to a lesser extent, its structural cousin IL-2 counteracted T-cell A(spont) by inhibiting the processing of caspase-3 and up-regulating Bcl-2 mRNA and protein levels. Cell division tracking confirmed that IL-15 did not rescue T cells from A(spont) by promoting proliferation but rather acted as a genuine survival factor. Addition of a gammac-blocking antibody to cytokine-conditioned cultures abrogated both apoptosis inhibition and Bcl-2 induction by IL-15, suggesting involvement of the IL-2Rgammac signal transduction pathway. Whereas cytokine-unprimed posttransplant T cells mounted inadequate responses to recall antigens, T cells conditioned with IL-15 expanded vigorously, indicating restoration of antigen-specific proliferation. CONCLUSIONS: T cells recovering after autologous PBPC transplantation are highly susceptible to spontaneous apoptosis in vitro. This phenomenon can be counteracted by the gammac-signaling cytokine IL-15. These findings suggest that IL-15 might be a promising immunomodulating agent to improve postgrafting T-cell function.

Actins↗
PubMed2001

The novel trinuclear platinum complex BBR3464 induces a cellular response different from cisplatin.

BBR3464 is a new platinum-based drug non cross-resistant with cisplatin. To characterise the cellular basis of BBR3464 cytotoxicity as opposed to cisplatin, we performed a comparative study of the two drugs in cisplatin-resistant neuroblastoma and astrocytoma cells. In both model systems, BBR3464 proved to be more potent than cisplatin and was able to overcome cisplatin resistance. The higher potency exhibited by BBR3464 correlated with an increased cellular platinum accumulation and DNA-adduct formation. At equitoxic doses, BBR3464 induced apoptosis to a lesser extent than cisplatin and failed to overcome the decreased susceptibility to cisplatin-induced apoptosis in cisplatin-resistant cells. Cell cycle analysis showed a dose-dependent G2/M arrest by BBR3464. In astrocytoma cells, cisplatin treatment resulted in the upregulation of p53, p21 and bax, while only p21 induction was observed after BBR3464 treatment. In cisplatin-resistant cells, the reduced sensitivity to cisplatin paralleled a resistance to the induction of p53/p21 pathway by cisplatin, while the same doses of BBR3464 induced p21 to a similar extent in the resistant cells as in the parental cells. In conclusion, BBR3464 induces a cellular response that is different from cisplatin, supporting the view that the two drugs act through different mechanisms. Our data indicate that BBR3464 may be a promising agent in the treatment of tumours unresponsive to cisplatin and with a non-functional p53.

Antineoplastic Agents↗
PubMed2001

Chemoprevention of DMBA-induced mammary cancer in rats by dietary soy.

This study was designed to assess the potential chemopreventive effect of the administration of a standardized soy extract, SOYSELECT, on 7,12-Dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats. Three groups, 24 females each, were used. Animals were fed either a phytoestrogen-free diet alone (control) or the same diet supplemented with 0.35% or 0.7% of soy extract. Treatment started at weaning and continued to the end of the study (24 weeks after DMBA administration). At day 50 of age all animals received via oral gavage 80 mg/kg DMBA. Only tumors subsequently classified as adenocarcinomas were considered for data evaluation. In rats on the soy diet, mammary tumors took a longer period of time to develop as compared to control rats. However, at the end of the study, no relevant difference in tumor incidence and multiplicity was observed among the groups. The most significant changes were seen between control and soy-treated groups when tumor dimension and results from histopathologic examination were considered. The latter, in fact, showed a dose-dependent reduction in the percentage of poorly differentiated tumors in treated animals. This change was statistically significant in animals receiving 0.7% soy. In addition, assessment of estrogen and progesterone receptor (ERalpha, PR) levels, revealed a significant reduction in the percentage of ERalpha and PR positive tumors in animals receiving 0.7% dietary soy, when compared to controls. Interestingly, genistein and daidzein plasma levels determined at the end of the study were within the range of those detected in people consuming large amounts of soyfoods.

9,10-Dimethyl-1,2-benzanthracene↗