Vascular endothelial growth factor (VEGF) in primate endometrium. Immunohistochemical patterns during the cycle and after chronic RU 486 treatment in cynomolgus monkeys.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
R Bukowski
Publications and source records attributed to R Bukowski.
Responses to T cell receptor/CD3 and interleukin-2 receptor stimulation are altered in T cells from B cell non-Hodgkin's lymphomas.
T cells infiltrating (T-TIL) B cell non-Hodgkin's lymphomas (NHL) are thought to represent a local host response to the tumor. However, tumor progression in the presence of this T cell infiltrate suggests that the T-TIL may be functionally impaired. To address this issue we determined whether response to stimulation of T-TIL from 25 patients with NHL through the T cell receptor (TCR/CD3) and the interleukin-2 (IL-2) receptor (IL-2R) was intact, since activation of these receptors is important for proliferation and cytokine production. Our results demonstrate defects in response to stimulation via TCR/CD3 and the IL-2R in T-TIL cells from patients with NHL that were not observed with T cells from the peripheral blood. T-TIL showed minimal proliferation to anti-CD3 and only modest proliferation to IL-2 alone or when combined with anti-CD3. Moreover, cytokine production in T-TIL was impaired since stimulation through the TCR/CD3 complex did not induce mRNA for interferon gamma (IFN gamma), IL-2, IL-4 or IL-10. The functional unresponsiveness of these cells may be linked to altered signalling through the TCR/CD3 since an abnormal tyrosine phosphorylation pattern was detected in T-TIL after stimulation with anti-CD3.
Adult↗
Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors.
PURPOSE: To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (i.v.) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, Princeton, NJ), a prodrug of etoposide, and VePesid (Bristol-Myers Squibb). PATIENTS AND METHODS: Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m2 of etoposide equivalent, was administered by constant rate infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high-performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (Cmax) and AUCinf of etoposide were contained within 80% to 125% for the long-transformed data. RESULTS: Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following i.v. administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on Cmax, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus time curve from zero to infinity (AUCinf) values. Mean terminal elimination half-life (t1/2), steady-state volume of distribution (Vss), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m2, and 17 mL/min/m2 after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia. CONCLUSION: With respect to plasma levels of etoposide, i.v. Etopophos is bioequivalent to i.v. VePesid.
Adult↗
Combination radiation and chemotherapy for the treatment of squamous cell carcinoma of the male and female urethra.
We report on 2 men and 2 women with locally advanced squamous cell carcinoma of the urethra who were treated with combination chemotherapy and radiation. Treatment consisted of 1,000 mg./M.2 5-fluorouracil plus 15 mg./M.2 mitomycin-C followed by 30 to 50 Gy. external beam radiation. The 2 women achieved durable complete responses, and are alive with no evidence of disease 94 and 43 months later, respectively. The men also had regional lymph node metastases, and 1 achieved complete response and has no evidence of disease 98 months posttreatment, while the other experienced partial response in the primary tumor and complete response in the involved inguinal nodes. The latter patient died of an unrelated cause with residual disease at 7 months. Only mild toxicity occurred in 3 patients. This regimen of chemotherapy and radiation is well tolerated and should be considered as primary therapy for invasive squamous cell carcinoma of the male and female urethra.
Adult↗
T cells from renal cell carcinoma patients exhibit an abnormal pattern of kappa B-specific DNA-binding activity: a preliminary report.
Recent data suggest that the poor induction of a T-cell response to human renal cell carcinoma (RCC) may be related to alterations in signal transduction pathways. We report that T cells from RCC patients have two alterations in kappa B motif-specific DNA-binding activity. The first alteration involves the constitutive expression of substantial kappa B-binding activity in nuclear extracts, which was observed in the electrophoretic mobility shift assay. The magnitude of kappa B activity in unstimulated patient T cells was similar to that observed in T cells from normal individuals that had been activated in vitro. On the basis of Western blotting experiments using antibodies to kappa B/Rel family proteins, the kappa B-binding activity constitutively expressed in T cells from RCC patients is composed mostly of the NF-kappa B1 (p50) subunit. The second abnormality in kappa B-binding activity in T cells from these patients is that RelA, a member of the Rel homology family which is part of the normal NF-kappa B complex, was not induced in the nucleus following activation. Western blotting analysis did not detect any RelA in nuclear extracts either before or after stimulation of T cells. The altered kappa B-binding activity in T cells from RCC patients may impair their capacity to respond normally to various stimuli.
Base Sequence↗
The impact of adjuvant nephrectomy on multimodality treatment of metastatic renal cell carcinoma.
Multimodality treatment of metastatic renal cell carcinoma with biological response modifiers and cytoreductive surgery has produced durable responses. The timing and impact of cytoreductive surgery on the success of immunotherapy require further study. We reviewed the treatment of 62 patients with metastatic renal cell carcinoma and primary tumors in place who qualified for multimodality treatment comprising adjuvant nephrectomy and biological response modifier protocols at our institution between 1987 and 1992. Of the patients 37 were scheduled to undergo initial adjuvant nephrectomy followed by biological response modifier therapy. A total of 25 patients underwent initial biological response modifier therapy with planned delayed adjuvant nephrectomy if a response to treatment was demonstrated. Of the 37 patients undergoing initial adjuvant nephrectomy, 8 (22%) were unable to enter induction of immunotherapy because of perioperative complications (1), medical contraindications (2), tumor progression (4) or death (1). Three patients in the initial adjuvant nephrectomy group (8%) had a partial response and the median survival in this group was 12 months (range 1 to 57). In the initial biological response modifier group 3 patients (12%) with an objective response (2 complete and 1 partial) to biological response modifier therapy underwent nephrectomy. The median survival for the initial biological response modifier group was 14 months (range 1 to 48). These results add to our understanding of the impact of adjuvant nephrectomy on patients with metastatic renal cell carcinoma considered for immunotherapy protocols.
Adult↗
Clinical status of the new cytoprotective agent, amifostine.
In summary, the data presented and reviewed at this symposium provide a strong rationale for the use of amifostine as a cytoprotective agent. Amifostine has been shown to reduce morbidity in cancer patients receiving radiation and chemotherapy without compromising the antineoplastic activity of the cancer therapies employed. Amifostine has been investigated extensively and appears particularly effective with cisplatin and cyclophosphamide, which operate via direct binding to the active species of these alkylating agents. It may also have a role in the protection of normal hematopoietic stem cells during bone marrow purging prior to bone marrow transplantation. Finally, amifostine may act synergistically with hematopoietic growth factors (ie, G-CSF) to protect and accelerate the recovery of hematopoietic stem cells exposed to high doses of radiation.
Agranulocytosis↗
Chemokine gene expression in the murine renal cell carcinoma, RENCA, following treatment in vivo with interferon-alpha and interleukin-2.
The expression of three chemoattractant cytokine (chemokine) messenger (m)RNAs in the murine renal cell carcinoma (RENCA) from mice treated with a combination of interferon-alpha (IFN-alpha) and interleukin-2 was examined and related to tumor infiltration by inflammatory leukocytes. Using a semi-quantitative reverse transcriptase polymerase chain reaction assay, mRNAs encoding the KC, JE, and IP-10 genes were all elevated in tumor tissue from mice treated systemically with IFN-alpha/interleukin-2 for 4 days. Similarly, the mRNA for tumor necrosis factor-alpha (TNF-alpha) was also increased in tumors from treated as compared to control animals. The same tumors showed a significant increase in Mac-1+ leukocytes, which correlated well with the increase in chemokine and TNF-alpha gene expression. The renal cell carcinoma tumor itself may be responsible for the expression of chemokine genes in the tumor bed following cytokine therapy. Cultures of freshly explanted RENCA cells expressed significant levels of chemokine mRNAs when stimulated in vitro with IFN alpha, IFN gamma, and/or interleukin-2, demonstrating that this tumor cell has potential for expression of these genes in vivo. In contrast, TNF-alpha expression was not detected in cultured tumor cells. Thus TNF-alpha may be expressed by infiltrating monocytes following exposure to recombinant cytokine therapy.
Animals↗
Interleukin 7 enhances the proliferation and effector function of tumor-infiltrating lymphocytes from renal-cell carcinoma.
Previous studies have documented the effects of IL2 on the growth and effector function of tumor-infiltrating lymphocytes (TIL) in cancer patients. Since IL7 is known to induce T- and NK-cell responses in the peripheral blood, we examined the immuno-enhancing effects of IL7 on TIL derived from human renal-cell carcinoma (RCC). Whereas IL2 induced the growth of freshly isolated TIL in vitro, IL7 was ineffective alone and failed to increase the total number of cells proliferating to IL2. However, IL7 did provide a proliferative signal to TIL that were initially expanded in culture with either IL2 or IL2/IL7 for 2 weeks. IL7 also induced the proliferation of CD4+ and CD8+ TIL lines that have specificity for RCC. The proliferative response induced by IL7 was independent of IL2, since anti-IL2 antibodies did not block IL7-induced proliferation of TIL. IL7 did cooperate with anti-CD3 stimulation for the induction of proliferation; however, the magnitude of this interaction was variable and the response usually additive. In addition, IL7 synergized with anti-CD3 to induce the secretion of IFN gamma from short-term-cultured TIL and from a TIL line. Although IL7 did not promote the development of a tumor-specific T-cell response from IL2-expanded TIL, IL7 enhanced lymphokine-activated killer (LAK) activity from some short-term-cultured TIL. These results illustrate that IL7 can potentiate the growth and production of IFN gamma from RCC-reactive TIL and, to a lesser extent, enhance IL2-induced LAK activity of TIL.
Carcinoma, Renal Cell↗
Nonrelativistic Lamb shift for a nonadiabatic many-particle system: An application to the dt micro ion.
Explore the source record for details and available documents.
Journal Article↗
The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. European Organization for Research on Treatment of Cancer--Genitourinary Group.
The prognostic value of the pathological response to combination chemotherapy of deeply invasive transitional cell cancer of the bladder was retrospectively assessed in 147 patients. Data were collected from 8 different centers. Patients were eligible if they had received intravenous combination chemotherapy followed by partial, total or radical cystectomy, and if they had a minimum followup of 2 years after the start of chemotherapy. Of the patients 90% received methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) or cisplatin plus methotrexate for a median of 3 courses (range 1 to 6). Of the 83 patients who were alive at analysis actuarial median followup was 30.5 months (range 13.2 to 85.6 months). A major pathological response (stage P0, Pis, Pa or P1) was achieved in 41.5% of the patients. Patients with a major pathological response (p stage less than 2) had a 5-year survival of 75% in contrast to 20% for the remaining nonresponding patients (p stage 2 or more). The survival of patients with a major pathological response was independent of whether the response was induced by 2 or more courses of chemotherapy, or whether it was induced by M-VAC in comparison with cisplatin plus methotrexate. Preoperative clinical assessments can identify nonresponding patients correctly and in these cases alternative treatment programs are required, since 80% will die of the disease. Moreover, if neoadjuvant chemotherapy is proved to increase survival, the data emphasize the importance of the response rate of the primary tumor and the need to investigate the optimal number of courses to induce the best response, preferably in the individual patient.
Actuarial Analysis↗
Characterization of a human renal cell carcinoma specific cytotoxic CD8+ T cell line.
Human renal cell carcinoma (RCC) is one of the tumors most sensitive to immunotherapy and in that regard it is similar to malignant melanoma. Clinical studies reporting responses to therapy suggested that a host immune response may be involved in the antitumor activity induced by immunotherapy in these tumors. Although detection of a specific T cell response to melanoma has been well documented, this has not been the case for RCC. The lytic response of interleukin-2 (IL-2) cultured tumor-infiltrating lymphocytes (TILs) from RCC has been nonspecific. However, in this report we describe a CD8+ TIL line derived from a primary RCC tumor that displays specificity for the autologous tumor. This line is lytic for autologous RCC but does not lyse autologous lymphoblasts, allogeneic RCC, or tumor cell lines of other histologic types. It also proliferates specifically to the autologous tumor in the absence of exogenous IL-2. However, the addition of low dose IL-2 to the cultures can significantly augment its proliferative response. When stimulated with autologous RCC but not allogeneic RCC the CD8+ line will produce interferon-gamma (IFN-gamma). It appears that recognition of RCC by this TIL line is through the TCR/CD3 complex because anti-CD3 antibody blocks the lytic activity, proliferation and IFN-gamma production of the line in response to the autologous tumor. Additional studies illustrate that cytotoxic T lymphocytes with apparent specificity for the autologous tumor are present in unseparated cultured TILs that can be detected by clonal analysis. Collectively these results suggest that there is a specific T cell response to human RCC.
CD8 Antigens↗
Phase I trial of dipyridamole with 5-fluorouracil and folinic acid.
We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.
Adult↗
Characterization of the cytolytic activity of CD4+ and CD8+ tumor-infiltrating lymphocytes in human renal cell carcinoma.
Previously we showed that IL2 expanded tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma mediated non-major histocompatibility complex-restricted cytotoxicity. Phenotypic analysis showed that cultured TILs were composed mostly of T-lymphocytes with varying numbers of CD4+, CD8+, and CD56+ (Leu19+) populations. Here we compared the cytolytic activity of the two predominant TIL subsets, CD3+CD4+ and CD3+CD8+, to that of the CD56+ populations. Using magnetic beads coated with antibodies to either CD4 or CD8, CD3+CD4+, and CD3+CD8+ TILs were isolated in a highly enriched form (greater than 92%) and could be expanded for over 40 days in vitro with 1000 units/ml IL2. In a 4-h 51Cr release assay the CD4+ and CD8+ TILs showed minimal lytic activity, whereas unseparated cells exhibited significant levels of non-major histocompatibility complex-restricted cytotoxicity. The lytic activity seen in the 4-h assay with unseparated TILs appeared to be related to the presence of CD56+ populations. With one exception none of the purified CD4+ or CD8+ TILs expressed any significant levels of CD56, while the unseparated TILs contained varying numbers of CD3+CD56+ and CD3-CD56+ populations. Cell-sorting experiments verified that the CD56+ populations were responsible for most of the lytic activity in 4 h even though CD3+CD56- cells represented the predominant cell type. Although CD3+CD56- TILs were minimally lytic in 4 h, we show here that both CD3+CD4+ and CD3+CD8+ subsets displayed substantial cytotoxicity in long-term assays. In the 18-h 51Cr release assay 5 of 6 CD4+ and 2 of 3 CD8+ TILs were lytic for the autologous tumor. In two cases, restimulation with the autologous tumor induced augmented cytolytic activity of TIL subsets and in one case induced lytic activity in 4 h. The cytotoxic activity of TIL subsets was further examined using a 72-h assay in which TILs were cocultured with a confluent layer of tumor cells. The degree of cytotoxicity was quantitated by measuring the amount of crystal violet dye that was incorporated by tumor cells which remained after the incubation period. CD4+ and CD8+ TILs typically caused greater than a 50% reduction of tumor cells in 3 days and the level of reduction was increased when IL2 was added to the cultures. All the CD4+ and CD8+ subset preparations were cytotoxic in the 3-day assay even though some were not lytic for certain targets in the 18-h 51Cr release assay.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
TIL from renal-cell carcinoma: restimulation with tumor influences proliferation and cytolytic activity.
TIL were cultured from human renal-cell carcinoma (RCC) in 1,000 U/ml rIL2 and restimulated with autologous tumor in efforts to establish which conditions would best expand the number of lymphocytes cytotoxic for autologous tumor. Greater cell yields resulted from multiple restimulations of TIL with autologous tumor. In most instances, these TIL lysed autologous tumor better than TIL grown in rIL2 alone. Enhanced proliferation was seen also after restimulation of TIL with allogeneic RCC as well as with tumor cells of non-renal origin. Although in some instances lysis of autologous tumor appeared to be specific, restimulation with autologous tumor did not consistently result in the generation of specific cytolytic T cells. Attempts to culture more specific cytolytic T cells by using 50 U/ml rIL2 were successful in expanding TIL with enhanced lytic activity; however, this activity was not specific for autologous tumor. The phenotype of the tumor-restimulated TIL generally did not change. In most of the TIL cultures, CD3+CD4+ cells were predominant with low numbers of CD3+Leu19+ cells and minimal numbers of CD3-Leu19+ cells. Thus, the cytotoxic response to tumor was mediated by T cells and not NK cells. Overall, our data indicate that restimulation of TIL with autologous tumor may be beneficial for growing larger numbers of cells which have increased lytic activity and for prolonging the presence of lytic activity among the expanded TIL.
Adult↗
The prognostic value of the pT-category after combination chemotherapy for patients with invasive bladder cancer who underwent cystectomy. EORTC-GU group.
Explore the source record for details and available documents.
Antineoplastic Combined Chemotherapy Protocols↗
Neoadjuvant intra-arterial chemotherapy in the treatment of advanced transitional cell carcinoma of the bladder: results and followup.
The long-term results of regional chemotherapy plus intra-arterial cisplatin with or without doxorubicin as an adjuvant before cystectomy and urinary diversion in patients with invasive transitional cell carcinoma of the bladder were evaluated. A total of 27 patients with T3aNxMo (8), T3bNxMo (14) and T4NxMo (5) disease participated in a phase II trial completed in 1985. Of the patients 19 received cisplatin and doxorubicin intra-arterially, and cyclophosphamide intravenously, and the remaining 8 received 70 to 100 mg. per m.2 cisplatin intra-arterially. A total of 19 patients underwent cystectomy after chemotherapy. Patients in this group had a pathological complete response (no evidence of disease after surgical restaging) or the presence of residual disease at operation that could (surgical complete response) or could not (pathological partial response) be completely resected. Of the 19 patients undergoing cystectomy surgical complete response was observed in 47.4%, pathological complete response in 26.3% and pathological partial response in 26.3%. At a median followup of 27 months for the group 66% of the patients with a surgical complete response, 100% with a pathological complete response and 40% with a pathological partial response were alive with no evidence of disease. The over-all survival for patients with a pathological or surgical complete response is 76.9%. In the patients not operated upon because of persistent or advanced disease after chemotherapy survival was brief (less than 4 months). Prolonged survival in patients achieving a pathological or surgical complete response with neoadjuvant chemotherapy occurs, and this modality may have a role in patients with invasive tumors.
Aged↗
Alternating non-cross-resistant chemotherapy for metastatic hormone-independent breast cancer.
A phase II clinical trial was designed to apply the treatment strategy of alternating non-cross-resistant chemotherapy regimens to patients with metastatic estrogen-receptor negative or hormone-refractory breast cancer. Twenty-six patients received Adriamycin and cyclophosphamide alternating at 3-week intervals with the combination of vinblastine, mitomycin-C, and 5-fluorouracil (5-FU). Toxicity was moderately severe. Two patients developed grade 2 and three developed grade 1 stomatitis. A single patient developed a WBC count of less than 1000/mm3, whereas five had a lowest recorded WBC count of 1,000-1,999/mm3. Two patients displayed thrombocytopenia of less than 50,000/mm3, one in conjunction with a fatal hemolytic-uremic syndrome. There were six complete and eight partial responses (PRs) for an objective response rate of 54% (64% of fully evaluable patients). The median survival after onset of protocol therapy was 13.3 months. These results are no better than those reported for other Adriamycin-containing regimens.
Adult↗