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Biomedical subjects

W Den Otter

Publications and source records attributed to W Den Otter.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of ocular squamous cell carcinomas in cattle with interleukin-2.

In total, 174 bovine ocular squamous cell carcinomas of varying sizes (20 to 2800 mm(2) in area) were treated daily with peritumoural injections of solvent, or solvent containing 5000 U, 20,000 U, 200,000 U, 500,000 U, 1 million U or 2 million U interleukin-2 (IL-2) for 10 days. The tumours were measured and clinically staged before treatment and at one, three, four, nine and 20 months after treatment. After 20 months, 14 per cent of the tumours treated with the solvent had regressed completely, a significantly smaller proportion than the 55 per cent treated with 5000 U IL-2, 52 per cent treated with 20,000 U IL-2, 58 per cent treated with 200,000 U IL-2, 50 per cent treated with 500,000 U IL-2, 69 per cent of tumours treated with 1 million U IL-2, 52 per cent treated with 2 million U IL-2. The tumours on the third eyelid and limbus were the most responsive.

Animals↗
PubMed2005

Galectins as markers of aggressiveness of mouse mammary carcinoma: towards a lectin target therapy of human breast cancer.

Galectins, beta-galactoside binding proteins, expressed selectively in human breast carcinoma are attractive targets to employ lectin-aimed therapeutics. We examined beta-galactoside binding potency of neoplastic cells using fluorescein-labelled synthetic glycoconjugates as probes for flow cytometry. As a result, surface beta-galactoside binding proteins/galectins were discovered on mouse mammary carcinoma cells in vitro and in vivo unlike non-malignant cells from the several tissues; and asialo-GM1 ganglioside carbohydrate part--containing probe was the most specific one. However, in liver and lung metastatic cells galectins seem to be expressed within cytoplasm and/or nuclei. Galectin expression correlated directly with aggressive tumour potential in the A/Sn transplantable model similar to findings in several human breast carcinoma cell lines. However, galectin expression was reduced during tumour progression in more aggressive forms of spontaneous BLRB mammary carcinomas like it was shown for human breast carcinoma specimens. Analysis of the histopathological data led, however, to the conclusion that galectin expression hardly might be a suitable marker of aggressiveness of heterogeneous mammary carcinomas as the observed level of galectin expression is influenced by the amount of the stroma in a tumour sample and/or probably, galectin expression inversely correlates with tumour aggressiveness during the initial and advanced steps of mammary tumour progression. We conclude that surface beta-galactoside binding proteins/galectins that are selectively expressed during mouse mammary carcinoma progression, similarly to human breast carcinomas, seem to be proper targets for asialo-GM1-vectored cytotoxics and our mouse model system might be a relevant instrument to further test novel modes of anti-breast cancer therapy.

Animals↗
PubMed2003

IL-2 loaded dextran microspheres with attractive histocompatibility properties for local IL-2 cancer therapy.

Biodegradable dextran microspheres (MS) were developed as a slow-release system for interleukin-2 (IL-2) to apply them for local IL-2 therapy of cancer. We describe the tissue reactions induced by these MS without or with IL-2 in rats. Dextran MS stain bright red-purple with the periodic acid Schiff (PAS), visualising the exact spot of IL-2 release and its relation to the histological reaction pattern. Subcutaneously injected MS always form a well-circumscribed deposit. In the first 2 days there is a PMN inflammation within the MS-deposit, but the surroundings show only a scanty inflammatory reaction. The PMN reaction is replaced by an abundant macrophage reaction in particular in the MS-deposit. At day 21 a fibrous capsule of about 50 mum surrounds the deposit. The effect of IL-2 administered in its free form is mainly vascular, with vascular dilatation, vascular leakage and oedema. It is remarkable that lymphocytes are present in the injection area already at day 2. When IL-2 releasing MS were used, the various reactions induced by IL-2 and MS were amplified leading to local necrosis. We conclude that neither placebo MS nor IL-2 leads to necrosis after subcutaneous injection in rats. In contrast, when IL-2 was released from MS, then massive necrosis was induced. This might be due to increased phagocytosis or changes in the micro-niche due to the release of humoral factors by the infiltrating cells. This is probably fortuitous for local IL-2 therapy of cancer, as massive necrosis of tumour cells can be expected to lead to an increased antitumour reaction.

Animals↗
PubMed2003

Comparison of the efficacy of local treatment of equine sarcoids with IL-2 or cisplatin/IL-2.

Local interleukin-2 (IL-2) is effective in a number of experimental animal models and in veterinary and human cancer patients without discomforting side effects. The primary goal of this study was to compare the therapeutic effects and side effects of the local intratumoral administration of five or ten low doses of IL-2 with those of a combination of cisplatin and a single high dose of IL-2 in the treatment of equine sarcoids. The therapeutic effect (complete and partial regression) of local cisplatin together with a single high dose of IL-2 was significantly better than the combined effect of low doses of local IL-2 administered daily over 5 or 10 days (80% and 43%, respectively; P=0.02). Cisplatin/IL-2 and low doses of IL-2 induced 53% and 14% complete regressions, respectively ( P=0.02). Histological changes after cisplatin/IL-2 treatment were far more pronounced than after IL-2 only treatment and in several cases showed an enormous eosinophilic infiltrate.

Animals↗
PubMed2001

In vitro biocompatibility of biodegradable dextran-based hydrogels tested with human fibroblasts.

The cytotoxicity of dextran T40, methacrylated dextran (dex-MA) and hydroxyethyl-methacrylated dextran (dex-HEMA), dextran-based hydrogel discs and microspheres, and their degradation products, was studied by measuring the cell proliferation inhibition index (CPII) on human fibroblasts in vitro. In addition, during the 72 h incubation period light-microscopic observations were performed daily. After 24 h of incubation with dextran and dex-HEMA polymers, the cells showed elongated or spider-like forms, some lipid droplets and intracellular granula, indicative of pinocytosis and internalization of the polymers. During the next two days, the fibroblasts' appearance did not change. Methacrylic acid (MAA), formed by hydrolysis of dex-HEMA, did not influence the cell morphology. Dex-HEMA polymer solutions with a low and high degree of substitution (DS) at 100 mg/ml caused a CPII of 30-40% after 72 h. This is less than 10% growth inhibition per cell cycle and statistically not different from the CPII induced by 100 mg/ml dextran T40. Growth inhibition induced by MAA was also low. The various dex-MA hydrogel discs caused similar low growth inhibition. Interestingly, hydrogel microspheres of dex-MA and dex-(lactate-)HEMA caused a CPII of only 0-20% after 72 h. The results presented in this study demonstrate that methacrylate-derivatized dextran hydrogels show good biocompatibility in vitro making these degradable biomaterials promising systems for drug delivery purposes.

Biocompatible Materials↗
PubMed2000

Local cytokine therapy of cancer: interleukin-2, interferons and related cytokines.

Local therapy with interleukin-2 (IL-2) and other cytokines may be a very effective way to treat cancer. This was the theme of the First Symposium on Local Cytokine Therapy of Cancer: Interleukin-2, Interferons and Related Cytokines, in Hamburg, 29 April-1 May 1999. The abstracts are published in Anticancer Research 19: 1995-2016 (1999). Here we present a report.

Animals↗
PubMed1999

Effect of local interleukin-2 treatment on spontaneous tumours of different immunogenic strength.

Transplantable tumour lines established from spontaneous tumours of BALB/c, CBA, and DBA/2 mice displayed different immunogenic strength. This report describes tumour susceptibility to interleukin-2 (IL-2) therapy in relation to tumour immunogenicity. The following tumour lines were used: X5, X6, and X9 mammary tumours of DBA/2, BALB/c, and CBA origin respectively, X7 carcinoma of BALB/c and X18 papilloma of CBA mice. Two spontaneous tumours of long transplantation history, SL2 lymphoma (SL2) of DBA/2 and Madison lung carcinoma M109 (M109) of BALB/c origin, were used as control systems. Experimental mice were transplanted with different inocula of tumour cells at day 0; treatment with IL-2 was initiated on days 1-3 or delayed until day 10 and consisted of daily injections of low doses of 5000 or 20,000 U/mouse given five times a week for a period of 3 weeks. Treatment of SL2 (2 x 10(4) cells injected i.p.) consisted of i.p. injections of 5000 or 20,000 U IL-2/mouse given on days 10-14 after tumour transplantation. IL-2 therapy of SL2-bearing DBA/2JIco mice resulted in a significant proportion of cures; however, no response to IL-2 treatment was achieved in SL2-bearing DBA/2CrIiw mice. BALB/c mice with the i.p. transplant of M109 responded to IL-2 treatment with 40% increase in lifespan. The low-dose IL-2 therapy of the five spontaneous tumours resulted, in general, in transient growth inhibition of the i.m. transplants of lines X5, X6, and X7 provided that IL-2 was administered locally. The therapeutic effect depended on the number of transplanted tumour cells, the best results being achieved at cell numbers close to the dose-inducing tumour growth in 50% of animals. We found that the spontaneously arising tumours responding to IL-2 treatment were all slowly growing and immunogenic (X6 and X7) or might have viral association (X5) and, as such, might express foreign antigens. The data suggest a correlation between tumour immunogenicity and the therapeutic effect. However, IL-2 can still exert some effect against tumours with negligible immunogenicity.

Animals↗
PubMed1999

Local low-dose IL-2 therapy.

Interleukin-2 (IL-2) is a powerful drug for treating cancer. However, it is only powerful if it is properly applied. That is, IL-2 should be applied at the tumor site, because at the transition of normal and malignant tissue are the tumor infiltrating cells. These should be activated by IL-2. Local application implies that IL-2 can be used in relatively low doses. It is becoming clear that even a single injection of IL-2 can cure cancer. IL-2 can also enhance the therapeutic effects of irradiation and Cisplatin. Locally applied IL-2 therapy is virtually non-toxic.

Animals↗
PubMed1998

Interleukin-2: hope in cases of cisplatin-resistant tumours.

To establish whether or not local low-dose recombinant interleukin-2 (rIL-2) therapy might result in therapeutic benefit for ovarian cancer patients treated with cisplatin, the antitumour effects of rIL-2 and of combined treatment with cisplatin and rIL-2 in a mouse ovarian tumour (MOT) model were studied. In addition, some possible mechanistic aspects underlying the observed antitumour responses were analysed. MOT cells were injected i.p. into syngeneic, immunocompetent, female C3HeB mice. Tumour-bearing mice received i.p. treatment with cisplatin, rIL-2 or both. The MOT tumour appeared to be hardly responsive to treatment with cisplatin only or rIL-2 only. In contrast, combined local treatment with low doses of cisplatin (1 and 5 mg/kg body weight) and rIL-2 (60000 U/day) resulted in an effective antitumour response in MOT-bearing mice. Complete rejection of the i.p. (local) tumour occurred in up to 60% of the cases. In vitro studies showed that cisplatin and rIL-2 do not have cumulative direct toxic effects on MOT cells. Mice cured after combined treatment with cisplatin and rIL-2 were not able to reject a rechallenge with tumour cells, indicating that these mice had not developed immunity to the tumour. Analysis of tumour-associated leucocytes, however, showed that combined treatment with cisplatin and rIL-2 did result in enhanced non-specific cytolytic activity of peritoneal leucocytes. We have thus demonstrated that, in the MOT model, combined local treatment with low doses of cisplatin and of rIL-2 is far more effective than therapy with cisplatin alone. Non-specific cytotoxicity of leucocytes appears to be involved in antitumour responses induced by combined treatment with cisplatin and rIL-2. These results suggest that, in human ovarian carcinoma, much better results may be obtained with the combined treatment of cisplatin and low (non-toxic) doses of rIL-2 than with cisplatin only. This may also apply to cisplatin-resistant ovarian carcinoma.

Animals↗
PubMed1998

Distribution of tumors in the retina in hereditary retinoblastoma patients.

We have compared the location of the ocular tumors in hereditary retinoblastoma in relation to the age of the patients at time of diagnosis. Eighty fundus drawings were analyzed from 59 hereditary patients containing I 59 tumors. At the time of diagnosis, indirect ophthalmoscopy was performed under general anaesthesia in all patients and standard drawings of the retina were made depicting the number and relative location of all tumors. The distance between the center of the tumor and the center of the macula was measured and plotted against the age of the patients at time of diagnosis. The results show that the distance between the center of the tumor and the center of the macula at time of diagnosis increases with age during the first seven months after birth.

Child, Preschool↗
PubMed1998

Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients.

PURPOSE: We evaluate the therapeutic effect of intravesical interleukin-2 (IL-2) on T1 papillary bladder carcinoma after incomplete transurethral resection. MATERIALS AND METHODS: After incomplete transurethral resection we treated 10 patients in whom the marker lesion was left in place with 3 x 10(6) Chiron units IL-2 in 50 ml. saline plus 0.1% human serum albumin. The solution remained in the bladder for 2 hours and it was instilled on 5 consecutive days. The effect of IL-2 treatment on the marker lesion was evaluated by cystoscopy and repeat biopsy of the marker site 2 months after treatment. In addition, the effect on the recurrence of bladder tumors was studied. RESULTS: At 2 months 8 of the 10 marker lesions (80%) had completely regressed and there were no tumor cells on repeat biopsy. Four patients remained tumor-free after 30 to 54 months. We noted no toxic effects. In 1 patient with a 7-year history of bladder cancer the marker was only partially regressed after 2 months. After removal of the marker this patient remained tumor-free at a followup of 54 months. CONCLUSIONS: To our knowledge this report represents the first study of the effect of IL-2 on marker lesions left in place after transurethral resection. The results indicate that IL-2 instillations are feasible, and the combination of transurethral resection and IL-2 instillation may have a powerful antitumor effect. The therapeutic effects may not simply be due to intravesical IL-2, because previous transurethral resection probably caused some influx of infiltrating cells and the marker may have had tumor associated antigens. Consequently these effects may be due to the interaction of tumor associated antigens, infiltrating cells and IL-2.

Administration, Intravesical↗
PubMed1998

Therapeutic potential of biological response modifiers against transplantable mouse tumors of spontaneous origin. II. Local interleukin 2 treatment of tumors of different immunogenic strength.

This report describes tumor susceptibility to interleukin 2 (IL-2) therapy in relation to tumor immunogenicity. The following lines recently established from spontaneous tumors were used: X5, X6, and X9 mammary tumors of DBA/2, BALB/c and CBA origin, respectively, X7 carcinoma of BALB/c and X18 papilloma of CBA mice. Two spontaneous tumors of long transplantation history, SL2 lymphoma (SL2) of DBA/2 and M109 Madison lung carcinoma (M109) of BALB/c origin, were used as control systems. Mice were transplanted with different inocula of tumor cells at day 0; IL-2 treatment was initiated on day 1-3 or 10 and consisted of daily injections of 5000 or 20,000 IU/mouse given 5 times a week for 3 weeks. SL2 (i.p. - 2 x 10(4) cells) treatment consisted of i.p. injections of 5000 or 20,000 IU IL-2 given on days 10-14. IL-2 therapy of SL2 bearing DBA/2JIco mice resulted in the significant proportion of cures; however, no response to IL-2 treatment was achieved in SL2 bearing DBA/2Crliw mice. BALB/c mice with the i.p. transplant of M109 responded to IL-2 treatment with 40% increase in lifespan. The low-dose IL-2 therapy of the 5 recently established tumors resulted, in general, in transient growth inhibition of the i.m. transplants of line X5, X6, and X7 provided IL-2 was administered locally. The therapeutic effect depended on the number of transplanted tumor cells, and the best results being achieved at cell numbers close to the dose inducing tumor growth in 50% of animals (TD50). We found that the tumors responding to IL-2 treatment were all slowly growing and immunogenic (X6 and X7) or might have viral association (X5) and as such might express foreign antigens.

Adjuvants, Immunologic↗
PubMed1997

Local low-dose interleukin-2 induces systemic immunity when combined with radiotherapy of cancer. A pre-clinical study.

Tumor recurrence and outgrowth of metastases limit the therapeutical effect of radiotherapy. We have tested whether these problems can be overcome by supplementing radiotherapy with locoregional interleukin-2 (IL-2) treatment. The SL2 lymphoma and the M8013 mammary carcinoma were used. Mice bearing a 10-day-old s.c. tumor were locally irradiated and were treated daily with IL-2 peritumorally for 5 or 10 days. Low-dose IL-2 therapy improved local response (LR) and increased disease-free survival (DFS) in both tumor models following either single-dose irradiation or fractionated irradiation. For example, 93% of SL2-bearing mice treated with single-dose irradiation and 10 days of IL-2 experienced long-term DFS, compared with 17% for irradiation alone (p < 0.0001). Additionally, treatment of one tumor with irradiation +IL-2 led to anti-tumor effects in a second, untreated tumor in 80% of SL2-bearing mice. LR was increased to 100% and DFS to 70% when the second, non-irradiated tumor was also treated with peritumoral IL-2. We conclude that supplementing local radiotherapy with low doses of IL-2 results in increased local tumor control and regression of distant, non-irradiated tumors. This type of radioimmunotherapy is a promising new approach for the clinic.

Animals↗
PubMed1997

Anti-tumor effects of local irradiation in combination with peritumoral administration of low doses of recombinant interleukin-2 (rIL-2).

The aim of this work was to improve radiotherapy results by immune stimulation. We tested the effects of a combination of radio- and immunotherapy, i.e., local low dose recombinant interleukin-2 (rIL-2) treatment, in two murine tumor models. Syngeneic tumors (SL2 lymphoma or M8013 mammary carcinoma) were induced subcutaneously on one or both flanks of mice. Irradiation was given either as a single dose (20 Gy) or fractionated (25 Gy) in 2 weeks. One or two cycles of rIL-2 were given concurrent with or subsequent to radiotherapy. One cycle of rIL-2 consisted of peritumoral injections administered on 5 consecutive days. Treatment effects were measured in terms of local tumor response and disease-free survival (DFS). The combined treatment modality was significantly better than treatment with either irradiation alone or rIL-2 alone. When tumors were inoculated on both flanks of the mice, combined radioimmunotherapy of one of the tumors also resulted in regression of the contralateral untreated tumor, indicating that a systemic anti-tumor immune reaction was induced. Additional rIL-2 injections did not enhance radiation toxicity. In conclusion supplementing irradiation with locally administered low doses of rIL-2 results in better local anti-tumor responses and DFS rates than either treatment alone without enhanced treatment toxicity. Furthermore, the local treatment induces a systemic anti-tumor reaction, influencing the growth patterns of a second, untreated tumor.

Animals↗
PubMed1997

Priming of the antitumor response promotes efficacy of interleukin-2 therapy.

We have studied the effect of active specific immunization (ASI) on the antitumor response induced by locoregional, low-dose interleukin-2 (IL-2) therapy. On day 0, mice were injected i.p. with viable, syngeneic tumor cells and with irradiated tumor cells (ASI). Low-dose IL-2 treatment was given i.p. for 5 consecutive days. ASI led to extended survival in two out of seven models tested. In these two models, enhanced efficacy was observed when both ASI and IL-2 were administered. In the five models in which ASI had no therapeutic value, ASI + IL-2 treatment was no more effective than IL-2 therapy. In the SL2 lymphoma model, use of ASI prior to IL-2 therapy given as early as days 1-5 led to at least 60% cure, whereas IL-2 therapy without ASI was only effective when administered after day 9. In the P815 mastocytoma model, however, ASI, IL-2, and the combination caused negative (suppressive) effects when administered on days 6-10. IL-2 administered on days 6-10 was therapeutically effective in this model when mice were treated with cyclophosphamide on day 6. In both the SL2 and the P815 tumor models, cured mice were specifically immune. The positive and negative effects observed were not due to the increased number of cells injected (non-specific inflammation) nor to possible antigenic alteration of the ASI cells by irradiation, as ASI with fragmented tumor cells was also effective in inducing synergy. Investigations into the underlying mechanism indicated that CD4+ cells play an important role. In total, the results indicate that ASI may be a good supplement to locoregional IL-2 treatment if care is taken to alleviate immunosuppressive activities.

Animals↗
PubMed1997

Histamine-stimulated expression of insulin-like growth factors in human glioma cells.

Glioma tumour growth is associated with the expression of insulin-like growth factors I and II (IGFs) and of both type I and type II IGF receptors. It has also been shown that IGFs can stimulate proliferation of cultured glioma cells. We previously reported that histamine too can stimulate the growth of glioma cells in vitro. In this report, we study whether the histamine-induced growth of G47 glioma cells is mediated by the IGFs. We found that histamine stimulates the expression of both IGF-I and IGF-II mRNAs, as determined by a semiquantitative in situ hybridization analysis. Furthermore, incubation of G47 cells with histamine also induced cellular immunostaining for IGF-II. It could be shown that IGF-I-stimulated proliferation is inhibited by IGFBP-3, which decreases the availability of IGFs for binding to the IGF receptors, and by beta-galactosidase, which may decrease IGF binding to the type II IGF receptor, but is not inhibited by the anti-type I IGF receptor monoclonal antibody alphaIR3. However, neither IGFBP-3 nor beta-galactosidase nor alphaIR3 inhibited the histamine-induced proliferation. These results show that the growth-stimulatory effect of histamine is accompanied by the induction of IGFs. This histamine-induced growth stimulation is not mediated by activation of cell surface IGF receptors, although intracrine activation of type II IGF receptors may be involved.

Brain Neoplasms↗