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Biomedical subjects

S Duensing

Publications and source records attributed to S Duensing.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cytogenetic studies in renal cell carcinoma patients receiving low-dose recombinant interleukin-2-based immunotherapy.

A variety of cytogenetic aberrations have been reported in sporadic and familial renal cell carcinoma. Rearrangements of the short arm of chromosome 3 (3p), trisomy 17, and nuclear hyperdiploidy have been reported to be common clonal chromosome changes. We analyzed a total of ten tumor-derived cell lines from patients who underwent nephrectomy for renal cell carcinoma employing conventional cytogenetics. All patients received an immunomodulatory therapy based on recombinant interleukin-2 (rIL-2). Tumor stage and grade, histo- and cytopathology, and patients' response to immunotherapy were assessed and correlated statistically to rearrangement of 3p, trisomy 17, and nuclear hyperdiploidy. Trisomy 17 as clonal aberration could be revealed only in papillary renal cell carcinoma, whereas tumors with compact or tubulopapillary growth pattern lacked this abnormality (p < 0.002). One of 3 patients with diploid or near-diploid karyotype (< or = 49 chromosomes) achieved a partial remission while two presented with stable disease after immunotherapy. In contrast, all 6 patients with tumor progression upon rIL-2-based immunotherapy revealed hyperdiploid (> 49 chromosomes) karyotypes. The correlation between hyperdiploidy and tumor progression was found to be statistically significant (p < 0.029). Interestingly, the only patient achieving an objective tumor remission after immunotherapy presented with a normal diploid karyotype. Our findings suggest tumor hyperdiploidy as an adverse prognostic factor in renal cell carcinoma patients receiving rIL-2-based immunotherapy.

Aged↗
PubMed1996

Exposure to vinblastine modulates beta 1 integrin expression and in vitro binding to extracellular matrix molecules in a human renal carcinoma cell line.

Solitary stroma-invading tumor cells expressing the ATP-binding cassette transporter P-glycoprotein have been reported to be associated with a significantly higher incidence of vessel invasion and lymph node metastases. In contrast to P-gp-mediated multidrug resistance (MDR) which has become well characterized over the last decade, little is known about further morphological and functional alterations in drug-resistant tumor cells. Binding of malignant cells to components of the extracellular matrix mediated by beta 1 integrins has been suggested to play a substantial role in the metastatic cascade. We studied alterations of beta 1 integrin expression and in vitro adhesiveness to extracellular matrix proteins of the human renal carcinoma line Caki-1 in comparison to the vinblastine resistant sublines Caki-1/V1 and Caki-1/V10 (cultured in the presence of 1 ng/ml and 10 ng/ml vinblastine, respectively). Both VLA-1 and VLA-2 receptors were acquired by the Caki-1/V10 subline, whereas untreated and Caki-1/VI cells lacked surface expression of these antigens. VLA-6 was found to be decreased in the vinblastine-resistant sublines. Attachment of drug-resistant Caki-1/V1 and Caki-1/V10 cells to collagen type I was significantly increased when compared to parental cells (p < or = 0.005). Significant differences in the attachment to type IV collagen were observed between Caki-1/V10 and untreated cells (p < or = 0.045). Both Caki-1/V1 and Caki-1/ V10 cells exhibited increased adhesion to fibronectin when compared to cells of the untreated line (p < or = 0.04). Whether an aberrant expression of beta 1 integrin receptors in resistant cells in combination with altered tumor cell adhesiveness is caused by MDR induction or whether it is an epiphenomenon of cytotoxic stress is unknown. Future studies will be needed to characterize the clinical relevance of MDR-associated changes in tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Biochemotherapy of advanced metastatic renal-cell carcinoma: results of the combination of interleukin-2, alpha-interferon, 5-fluorouracil, vinblastine, and 13-cis-retinoic acid.

We conducted a phase I/II clinical trial evaluating the sequential outpatient combination of S.C. recombinant human interleukin-2 (rIL-2; given at 10 MIU/m2 b.i.d. on days 3-5 weeks 1 and 4 and at 5 MIU/m2 on days 1, 3, and 5 of weeks 2 and 3), s.c. recombinant human alpha-interferon (rIFN-alpha; given at 6 MIU/m2 on day 1 of weeks 1 and 4 and on days 1, 3, and 5 of weeks 2 and 3 and at 9 MIU/m2 on days 1, 3, and 5 of weeks 5-8), i.v. bolus 5-fluorouracil (5-FU; given at 1,000 mg/m2 once weekly during weeks 5-8), and i.v. bolus vinblastine (given at 6 mg/m2 once weekly during weeks 5 and 8) in conjunction with p.o. 13-cis-retinoic acid (13-C-RA; given at 35 mg/m2 daily during weeks 1-8). Therapy was always given in the outpatient setting. Grade 3 constitutional symptoms (malaise, chills, fevers, anorexia) were observed in 4%-8% of treatment cycles and required a 50% reduction in the doses of rIL-2 and rIFN-alpha. None of the patients experienced major 5-FU-related toxicities such as severe diarrhea and/or stomatitis; up to 20% of patients developed vinblastine-associated peripheral polyneuropathy, which was reversible after the cessation of therapy. 13-cis-Retinoic acid produced no significant side effect; no toxic death occurred. Among 24 patients with progressive metastatic disease, there were 4 complete remissions (lung, lymph nodes) and 6 partial remissions (lung, pleura, liver, lymph nodes, and peritoneal carcinosis), for an overall objective response rate of 42% (95% confidence interval, 22%-63%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1995

Chemoimmunotherapy of advanced malignant melanoma: sequential administration of subcutaneous interleukin-2 and interferon-alpha after intravenous dacarbazine and carboplatin or intravenous dacarbazine, cisplatin, carmustine and tamoxifen.

Both chemotherapy and interleukin-2 and/or interferon-alpha produce objective responses in a proportion of advanced malignant melanoma patients. While duration of response to chemotherapy is short, i.e. usually below 4 months, immunotherapy has resulted in a small number of long-lasting remissions in patients with metastatic melanoma. In two consecutive phase II trials in a total of 67 patients, we assessed the potential synergism between both modalities, i.e. chemo- and immunotherapy. Treatment consisted of intravenous (i.v.) carboplatin (CBDCA, 400 mg/m2) and dacarbazine (DTIC, 750 mg/m2) given twice (i.v. bolus over 30 min) at 3-week intervals, or 4 cycles of DTIC (220 mg/m2 i.v. 3 days), cisplatin (DDP, 35 mg/m2 i.v. 3 days), carmustine (BCNU, 150 mg/m2 i.v. cycles 1 and 3) and tamoxifen (TAM, 20 mg oral/daily) at 3-week intervals. Chemotherapy was followed by immunotherapy with combined subcutaneous (s.c.) interleukin-2 (rIL-2) and SC interferon-alpha 2 (rIFN-alpha). Among 40 patients who received a full cycle of chemotherapy with CBDCA/DTIC and sequential immunotherapy, there were 3 (7.5%) complete remissions (CRs) with a median duration of 19 months (range 13-26+). Partial remissions (PRs) were noted in 11 (27.5%) patients with a median response duration of 8 (range 5-14) months. Among 27 patients who received DTIC/DDP/BCNU/TAM and rIL-2/rIFN-alpha, there were 3 (11%) complete remissions and 12 (44.5%) partial remissions. Duration of complete and partial remissions ranged from 9+ to 13+ (median, 11+), and 5 to 15+ (median, 7+) months, respectively. Chemotherapy produced mostly moderate toxicity. Thrombocytopenia was common with the nadir after a median time of 18 days following start of CBDCA/DTIC and DTIC/DDP/BCNU, respectively. 10 patients required transfusion of thrombocytes. Nausea and vomiting due to chemotherapy were well tolerated using concomitant ondansetrone (8 mg i.v.). Immunotherapy was self-administered at home with mild to moderate side effects; malaise, fever, chills, nausea/vomiting, diarrhoea, anorexia and arthralgias were most frequent, but were spontaneously reversible after ending rIL-2/IFN-alpha. A mean 87 and 88% of the projected doses of rIL-2 and rIFN-alpha were administered on either protocol. There were no life-threatening complications and no treatment-related deaths. The sequential combination of chemotherapy and rIL-2 plus rIFN-alpha had at least additive therapeutic activity against metastatic malignant melanoma. The schedules produced long-lasting remissions and were tolerated well overall. These trials substantiate a potential role for low to intermediate dose immunotherapy in maintaining and consolidating therapeutic effects of chemotherapy in metastatic melanoma.

Administration, Cutaneous↗
PubMed1995

In vivo distribution of integrins in renal cell carcinoma: integrin-phenotype alteration in different degrees of tumor differentiation and VLA-2 involvement in tumor metastasis.

We studied 23 renal cell carcinomas and two normal kidney tissues by immunohistochemistry using monoclonal antibodies against subunits of the VLA integrins (VLA-1 to VLA-6) and CD51. All integrins investigated in our study, except VLA-4 (ubiquitous negative), were distributed in different patterns in tumors assayed. We found a correlation between VLA-2 expression and site of tissue; primary tumor cells expressed no VLA-2 integrin, whereas tumor cells from metastatic tissues exhibited VLA-2 positivity (P < .009). Additionally, the expression of VLA-3 and VLA-5 correlated with tumor grading; both integrins were undetectable in G1 tumors but widely expressed in G2 and G3 tumors (VLA-3, p < .000; VLA-5, p < .005). Our results suggest that VLA-2 integrin is involved in metastasis of RCC and that poorly differentiated tumor cells have a different integrin phenotype when compared to normal or highly differentiated tumor cells.

Adult↗
PubMed1995

Lymphocyte-conditioned medium in combination with interleukin-2 effectively induces antitumour autoimmunity by adoptive transfer of short activated killer (SHAK) cells.

In this study, effective antitumour immunity was transferred by autologous short activated killer (SHAK) cells induced over four hours with lymphocyte conditioned medium (LCM) and recombinant interleukin-2 (rIL-2). Among eight patients with progressive metastatic renal cell carcinoma refractory to standard therapy, there were six objective tumour responses to SHAKs. Progression-free survival ranged from 0 to 8+ months, and overall survival ranged from 2 to 14+ months, with a median of 9+ months. Systemic toxicity of SHAKs was limited to flulike symptoms. Patient SHAKs provided a tumour-specific immunity, both cellular and humoral (expression and secretion of secondary cytokines, including IL-2, GM-CSF, INF-gamma and TNF-alpha), far superior to rIL-2 activated killer cells.

Adoptive Transfer↗
PubMed1994

Cytokine-based biotherapy of gastrointestinal tumors.

Over the past 20 years the administration of cytokines has emerged as an important fourth modality for the treatment of human cancer. Advances in the field of therapy of gastrointestinal tumors have become a major focus of current research, given the lack of progress of conventional antineoplastic therapy in most of these tumors. Among the heterogeneous group of gastrointestinal malignancies, novel therapeutic strategies have been employed for each individual tumor type, and cytokines (interferon-alpha) have gained an established role in the treatment of advanced carcinoid tumors. Although our understanding of the mechanisms of biological response modification is still limited, further improvement in the management of gastrointestinal malignancies can be expected from multimodality therapy regimens employing cytokines in combination with other biological response modifiers, chemotherapeutic agents, active-specific immunotherapy, and immunotoxin- and radionuclide-conjugated monoclonal antibodies. A wide range of clinical and preclinical studies have been conducted in colorectal carcinoma; however, potential therapeutic benefit of cytokine-based biotherapy has not been fully defined. Therefore, largescale, i.e., multicenter, studies are required to quantify the potential therapeutic effects of cytokines in gastrointestinal tumors.

Clinical Trials as Topic↗
PubMed1994

In vivo time and dose dependency of interleukin-6 secretion in response to low-dose subcutaneous recombinant interleukin-2.

Serum concentrations of Interleukin-6 (IL-6) were determined in renal cell carcinoma patients treated with low-dose subcutaneous human recombinant interleukin-2 (rIL-2). In all patients, administration of rIL-2 resulted in a significant increase in IL-6 serum levels to peak values within 4 to 6 hours as measured by enzyme-linked immunosorbent assays (ELISA). Repetitive administration of rIL-2 induced significantly lower IL-6 serum peaks when compared to the initial administration of rIL-2. Cumulative IL-6 release, as expressed by the area under the concentration curve (AUC), appeared to be independent of rIL-2 dose distribution (10 million IU rIL-2/m2 versus 20 million IU rIL-2/m2), and IL-6 serum peaks showed no direct dose dependency. Prior rIL-2 immunotherapy had no measurable effect on rIL-2 induced IL-6 release, while steroids resulted in a significant suppression of secondary IL-6 did not correlate with response to rIL-2 therapy or survival of rIL-2 treated renal cell carcinoma patients.

Aged↗
PubMed1993

Limited efficacy of interferon-alpha and vinblastine as second line biochemotherapy regimen in patients with progressive metastatic renal cell carcinoma.

We report on thirty-four patients with metastatic renal cell carcinoma who were treated with a combination of subcutaneous recombinant interferon-alpha and intravenous vinblastine upon progression after previous antineoplastic therapy. Pretreatment included chemotherapy (n = 3), hormonal therapy (n = 6) and immunotherapy (interleukin-2/interferon-alpha, n = 25). In this study, treatment courses consisted of subcutaneous doses thrice weekly of recombinant interferon-alpha at 6 million U/m2 (20 patients, group 2), respectively. Treatment was given over 8 consecutive weeks. Additionally, in all patients, vinblastine was administered intravenously at a dose of 6 mg/m2 in weeks 2, 5 and 8. Of 14 patients treated in group 1, one had a partial response for 6 months (overall response rate 7.14%; 95% confidence interval, 0.18-33.87%), and four had disease stabilization (median duration, 5.0 months). Of 20 patients treated in group 2, there was one patient who achieved a complete response (response duration, 34+ months); in addition, two patients had a partial response (median response duration, 10.5+ months; overall response rate, 15%; 95% confidence interval 3.21-37.89%), and 13 patients exhibited disease stabilization (median duration 5.9+ months). Response rates showed no significant differences when comparing treatment results in patients in group 1 vs group 2. In contrast, significantly less patients treated in group 2 had progressive disease (p = 0.024), as compared to patients in group 1. This treatment combination was overall well tolerated with low to moderate systemic toxicity. In addition, there were no significant differences in frequency or intensity of therapy-related systemic toxicities when comparing patients in group 1 and group 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Pretreatment natural killer antigen density correlates to clinical response in tumor patients receiving long-term subcutaneous recombinant interleukin-2 and recombinant interferon-alpha.

We evaluated density of the natural killer (NK) cell-associated CD56 antigen on circulating NK cells of 47 patients with advanced renal cell carcinoma. Patients received a combination of low-dose subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha) as home therapy. Antigen density of CD56 before therapy was 2.2-fold higher (P < 0.005) in patients who subsequently achieved a complete or partial remission when compared with patients who presented with progressive disease on therapy. After a 6-week treatment cycle, NK cells of treatment responders expressed significantly (2.1-fold; P < 0.005) more CD56 antigens than NK cells in nonresponding patients. These results suggested a potential role of both pre- and posttreatment NK antigen density levels as a biologic correlate to treatment response.

Antigens, CD↗
PubMed1992

Biologic and therapeutic efficacy of mafosfamide in patients with metastatic renal cell carcinoma.

It is well known that oxazaphosphorines [e.g., cyclophosphamide and 4-hydroperoxycyclophosphamide (mafosfamide)] are potent immunosuppressive agents. Under the proper conditions, they can potentiate immune responses as well. Immunomodulation represents a major breakthrough in the management of chemotherapy-resistant tumors. Thus, we evaluated the clinical and laboratory sequelae of low to intermediate doses (100-1000 mg/m2) of mafosfamide administered to 16 patients. Four weeks after therapy, one patient had a complete remission, eight patients presented with stable disease, and seven patients did not respond. Clinical and laboratory toxicity was mild and totally reversible, and therapy was well tolerated in all patients. Analyses of phenotypic cell surface antigens on circulating peripheral blood mononuclear cells showed inconsistent alterations of the CD4/CD8 ratio, initial depletion with later rebound of CD8+ cells, increase of CD20+ cells, and a mafosfamide dose-dependent regulation of natural killer-like cells as characterized by CD16 and CD56 positivity. Cell-mediated cytotoxicity against K562 target cells peaked 1 day after therapy and was most pronounced in patients who had received 300 mg/m2 mafosfamide, whereas cytotoxicity against Daudi targets was essentially unchanged, consistent with an increase in natural killing activity without augmentation of lymphokine activated killing. We conclude that mafosfamide administration at low to intermediate doses can be performed with good safety and tolerance; immunophenotypic analyses and cytotoxicity assays showed most pronounced alterations in patients receiving low doses of mafosfamide. These observations support the use of mafosfamide in the attempt to augment antitumor immune responses.

Adjuvants, Immunologic↗
PubMed1979

The Cheshire Cat effect.

Designing a binocular-rivalry exhibit for the Exploratorium resulted in the observation of some interesting phenomena. Under conditions of binocular rivalry, motion in the field of one eye can trigger suppression of the other visual field as a whole or in parts. This suppression sometimes occurs only in the area of motion. Subparts of a suppressed area often remain in the visual field. Conversely, moving an object into the suppressed area of a visual field can elicit dominance of that object alone, with the rest of the field remaining suppressed. The suppression of partial areas of the visual field of each eye can occur simultaneously.

Dominance, Cerebral↗
PubMedDate not supplied

Participation of Survivin in mitotic and apoptotic activities of normal and tumor-derived cells.

Survivin is a member of the inhibitor of apoptosis (IAP) gene family, containing a single baculovirus IAP repeat (BIR) and no RING finger, that is expressed in many human cancers. Although it has been proposed to be involved in mitotic and cytokinetic processes, its functional subcellular distribution in the cytoplasm and nucleus, and its binding to centrosomes, spindle fibers, and centromeres in relation to these processes, is not fully resolved. We have analyzed the localization of Survivin in normal (Detroit 551, IMR-90) and tumor-derived (HeLa, Saos-2) cell lines, and found that it does colocalize with centrosomes in the cytoplasm during interphase, then moves to centromeres during mitosis, and finally localizes to the midbody spindle fibers during telophase. However, Taxol, a popular microtubule stabilizing agent that is frequently used in the study of these processes, severely disrupted the localization of Survivin. Taxol treatment of cells promoted extensive relocalization of Survivin with alpha-tubulin on microtubules during either interphase or mitosis. Survivin antisense oligonucleotide markedly sensitized HeLa cells to cell death induced by agents acting at the level of cell surface receptor (Fas pathway) or at the level of mitochondria (etoposide). HeLa cell death induced by Survivin antisense oligonucleotide could be partially complemented by Deterin, the Drosophila homolog of Survivin (Jones et al. [2000] J. Biol. Chem. 275:22157-22166). Reciprocally, a chimera of the Deterin BIR domain and Survivin C-terminus could rescue Drosophila Kc cells from death induced by transfection of a human caspase-7-expressing plasmid. These results indicate common components of Survivin and Deterin antiapoptotic action in the vertebrate and invertebrate phyla.

Animals↗