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  1. Article: Isolated limb perfusion with TNF alpha and melphalan in a rat osteosarcoma model: a new anti-tumour approach.

    Manusama, E R / Stavast, J / Durante, N M / Marquet, R L / Eggermont, A M

    European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology

    1996  Volume 22, Issue 2, Page(s) 152–157

    Abstract: Isolated limb perfusion (ILP) with TNF alpha, IFN gamma and melphalan causes impressive tumour reduction in patients with irresectable soft tissue sarcomas with a high limb salvage rate. Since this therapy could be of value in patients with progressive ... ...

    Abstract Isolated limb perfusion (ILP) with TNF alpha, IFN gamma and melphalan causes impressive tumour reduction in patients with irresectable soft tissue sarcomas with a high limb salvage rate. Since this therapy could be of value in patients with progressive osteosarcoma, we performed a study in an osteosarcoma tumour model in the rat. The ROS-1 osteosarcoma was implanted s.c. in the hind leg of WAG rats. Rats were divided in four groups: rats that underwent ILP with perfusate alone, TNF alpha alone, melphalan alone or their combination. Almost all rats, treated with a sham ILP or a perfusion with 40 micrograms melphalan, showed progressive disease (PD) (6/6 and 5/6). After perfusion with 50 micrograms TNF alpha alone a varied response was observed: 2/6 PD, 2/6 no change (NC) and 2/6 a complete remission (CR). After combined perfusion: 3/6 rats had a partial remission and 3/6 a CR. The best and most consistent responses are obtained by combining TNF alpha and melphalan. The discrepancy with the in vitro sensitivity of ROS-1 indicates that indirect effects are important in this tumour model.
    MeSH term(s) Animals ; Antineoplastic Agents, Alkylating/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Male ; Melphalan/administration & dosage ; Osteosarcoma/drug therapy ; Osteosarcoma/therapy ; Perfusion/methods ; Rats ; Rats, Inbred Strains ; Treatment Outcome ; Tumor Necrosis Factor-alpha/administration & dosage
    Chemical Substances Antineoplastic Agents, Alkylating ; Tumor Necrosis Factor-alpha ; Melphalan (Q41OR9510P)
    Language English
    Publishing date 1996-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632519-1
    ISSN 0748-7983
    ISSN 0748-7983
    DOI 10.1016/s0748-7983(96)90671-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Synergistic antitumour effect of recombinant human tumour necrosis factor alpha with melphalan in isolated limb perfusion in the rat.

    Manusama, E R / Nooijen, P T / Stavast, J / Durante, N M / Marquet, R L / Eggermont, A M

    The British journal of surgery

    1996  Volume 83, Issue 4, Page(s) 551–555

    Abstract: The efficacy of isolated limb perfusion (ILP) for 'intransit' metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) alpha. A rat sarcoma tumour model was, ... ...

    Abstract The efficacy of isolated limb perfusion (ILP) for 'intransit' metastases from malignant melanoma and irresectable soft tissue sarcoma has been improved considerably by the addition of tumour necrosis factor (TNF) alpha. A rat sarcoma tumour model was, therefore, developed to evaluate the effects of TNF-alpha, melphalan and the combination of these drugs in the treatment of sarcoma. In BN rats bearing the non-immunogenic BN 175 sarcoma ILPs were performed with perfusate only, TNF-alpha, melphalan alone, or in combination when tumours had grown to approximately 1.5 cm in diameter. All rats treated with sham perfusion or perfusion with 50 micrograms TNF-alpha showed progressive disease. After perfusion with 40 micrograms melphalan no change in tumour diameter was observed in any rats at 4 days. After a combined perfusion with 40 micrograms melphalan and 50 micrograms TNF-alpha complete remission was noted in 12 of 16 rats. This synergistic effect in vivo between relatively ineffective doses of TNF-alpha and melphalan was not observed in vitro.
    MeSH term(s) Animals ; Chemotherapy, Cancer, Regional Perfusion ; Dose-Response Relationship, Drug ; Drug Synergism ; Hindlimb ; Humans ; Male ; Melphalan/administration & dosage ; Rats ; Sarcoma, Experimental/therapy ; Tumor Necrosis Factor-alpha/administration & dosage
    Chemical Substances Tumor Necrosis Factor-alpha ; Melphalan (Q41OR9510P)
    Language English
    Publishing date 1996-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2985-3
    ISSN 0007-1323 ; 0263-1202 ; 1355-7688
    ISSN 0007-1323 ; 0263-1202 ; 1355-7688
    DOI 10.1002/bjs.1800830438
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The value of in vivo electrophysiological measurements for monitoring functional adaptation after massive small bowel resection in the rat.

    Wolvekamp, M C / Durante, N M / Meyssen, M A / Bijman, J / de Jonge, H R / Marquet, R L / Heineman, E

    Gut

    1993  Volume 34, Issue 5, Page(s) 637–642

    Abstract: The process of functional adaptation after extensive small bowel resection is complex and imprecisely understood. In vivo electrophysiological measurements for monitoring the functional adaptive process after massive small bowel resection in Brown-Norway ...

    Abstract The process of functional adaptation after extensive small bowel resection is complex and imprecisely understood. In vivo electrophysiological measurements for monitoring the functional adaptive process after massive small bowel resection in Brown-Norway rats were evaluated. Rats underwent either a sham operation (SH) or a 90% small bowel resection (SB). Standard rat chow was fed in unlimited quantities. At three or 10 weeks after operation, jejunal and ileal transepithelial potential differences (PD, mV) were determined. Electrogenic ion transport in the villus was measured after glucose (sodium coupled active glucose absorption; PD-glu) and in the crypt, after theophylline infusion (theophylline stimulated chloride secretion; PD-theo). Biopsies were taken simultaneously. Each experimental group consisted of three to five animals. At three weeks the PD-theo and PD-glu in SB rats were significantly lower than in SH rats in both jejunal and ileal segments. At 10 weeks PD-theo and PD-glu were significantly diminished in the jejunal segment of the SB rats compared with the SH rats. The values of PD-theo and PD-glu in the ileal segments were, however, no longer different between the two groups. Three and 10 weeks after operation the length of the villi in the SB group was increased significantly compared with the SH controls. These results indicate that in the early phase of adaptation in vivo electrophysiological variables do not correlate with histological changes in the SB rats. This might be due to cell immaturity resulting from an increased rate of cell turnover or lack of intercellular tight junctions. This hypothesis is supported by a recovery of PD responses in the ileum 10 weeks after resection.
    MeSH term(s) Adaptation, Physiological/physiology ; Animals ; Electrophysiology ; Epithelium/pathology ; Epithelium/physiology ; Ileum/pathology ; Ileum/physiology ; Intestine, Small/physiology ; Intestine, Small/surgery ; Ion Transport ; Jejunum/pathology ; Jejunum/physiology ; Male ; Postoperative Period ; Rats ; Rats, Inbred Strains ; Time Factors
    Language English
    Publishing date 1993-05
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80128-8
    ISSN 1468-3288 ; 0017-5749
    ISSN (online) 1468-3288
    ISSN 0017-5749
    DOI 10.1136/gut.34.5.637
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats.

    Schellens, J H / Van de Vrie, W / Loos, W J / Kolker, H J / Verweij, J / Stoter, G / Durante, N M / Eggermont, A M

    Cancer chemotherapy and pharmacology

    1997  Volume 41, Issue 1, Page(s) 48–52

    Abstract: The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 ... ...

    Abstract The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of correlation (> 0.8) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured.
    MeSH term(s) Adenocarcinoma/blood ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Colonic Neoplasms/blood ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Dihydropyridines/administration & dosage ; Dihydropyridines/pharmacokinetics ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Kidney/metabolism ; Neoplasm Transplantation ; Pyridines/metabolism ; Rats ; Rats, Inbred Strains
    Chemical Substances Antineoplastic Agents ; Dihydropyridines ; Pyridines ; niguldipine (Z81N45O25Z)
    Language English
    Publishing date 1997
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 6820-2
    ISSN 1432-0843 ; 0344-5704 ; 0943-9404
    ISSN (online) 1432-0843
    ISSN 0344-5704 ; 0943-9404
    DOI 10.1007/s002800050706
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model.

    Van de Vrie, W / Schellens, J H / Loss, W J / Kolker, H J / Verwey, J / Stoter, G / Durante, N M / Eggermont, A M

    Journal of cancer research and clinical oncology

    1996  Volume 122, Issue 7, Page(s) 403–408

    Abstract: The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the ... ...

    Abstract The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (+/- 19 SD) ng/ml in plasma and 925 (+/- 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (+/- 6 SD) ng/ml and 289 (+/- 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.
    MeSH term(s) Adenocarcinoma/blood ; Adenocarcinoma/drug therapy ; Adenocarcinoma/metabolism ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Biotransformation ; Colonic Neoplasms/blood ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Dihydropyridines/administration & dosage ; Dihydropyridines/pharmacokinetics ; Drug Resistance, Multiple ; Drug Screening Assays, Antitumor ; Drug Synergism ; Epirubicin/administration & dosage ; Male ; Neoplasm Transplantation ; Rats ; Rats, Inbred Strains ; Tumor Cells, Cultured
    Chemical Substances Dihydropyridines ; Epirubicin (3Z8479ZZ5X) ; niguldipine (Z81N45O25Z)
    Language English
    Publishing date 1996
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 134792-5
    ISSN 1432-1335 ; 0171-5216 ; 0084-5353 ; 0943-9382
    ISSN (online) 1432-1335
    ISSN 0171-5216 ; 0084-5353 ; 0943-9382
    DOI 10.1007/bf01212879
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: In vitro and in vivo chemosensitizing effect of cyclosporin A on an intrinsic multidrug-resistant rat colon tumour.

    Van de Vrie, W / Gheuens, E E / Durante, N M / De Bruijn, E A / Marquet, R L / Van Oosterom, A T / Eggermont, A M

    Journal of cancer research and clinical oncology

    1993  Volume 119, Issue 10, Page(s) 609–614

    Abstract: Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on ... ...

    Abstract Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorubicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg-1 day-1. This resulted in whole-blood CsA levels above 2 mumol/l, while intratumoral CsA levels amounted to 3.6 mumol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Adenocarcinoma/drug therapy ; Adenocarcinoma/metabolism ; Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carrier Proteins/biosynthesis ; Colchicine/administration & dosage ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Cyclosporine/pharmacokinetics ; Cyclosporine/therapeutic use ; Drug Resistance/genetics ; Drug Synergism ; Male ; Membrane Glycoproteins/biosynthesis ; Neoplasm Proteins/biosynthesis ; Rats ; Rats, Inbred Strains ; Tumor Cells, Cultured/drug effects ; Verapamil/administration & dosage
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Carrier Proteins ; Membrane Glycoproteins ; Neoplasm Proteins ; Cyclosporine (83HN0GTJ6D) ; Verapamil (CJ0O37KU29) ; Colchicine (SML2Y3J35T)
    Language English
    Publishing date 1993
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 134792-5
    ISSN 1432-1335 ; 0171-5216 ; 0084-5353 ; 0943-9382
    ISSN (online) 1432-1335
    ISSN 0171-5216 ; 0084-5353 ; 0943-9382
    DOI 10.1007/bf01372724
    Database MEDical Literature Analysis and Retrieval System OnLINE

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