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H R Hendriks

Publications and source records attributed to H R Hendriks.

15 recordsLinked to original sources
PubMed1992

Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts.

The antitumour activity of the investigational agent vinblastine-isoleucinate (V-LEU) was compared with vintriptol, another investigational agent of the same series of vinblastine-23-oyl amino acid derivatives, and vinblastine, their clinically active parent compound, in a panel of nine human tumour xenografts growing subcutaneously in nude mice. Compounds were administered intravenously at equitoxic doses twice weekly. As assessed by optimal tumour growth inhibition and tumour growth delay, vinblastine, V-LEU and vintriptol exhibited antitumour activity in 8/9, 7/9 and 4/7 human tumour xenografts, respectively. When growth curves and numbers of complete remissions were compared, V-LEU was the most active agent in two malignant melanoma lines (THXO and LOX p28) and two small cell lung carcinoma lines tested (LXFS 538 and WX 322), whereas vinblastine was more active against the two colorectal carcinomas (CXF 243 and CXF 280). Notably, the non small cell lung carcinoma (NSCLC) line AHXOL was resistant to the three agents. The results of this study suggest that V-LEU was as active as vinblastine in most tumour lines, exhibiting superior antitumour activity in malignant melanoma, SCLC and breast cancer lines. The decision to bring this compound into clinical trial shall await further confirmation of these preclinical results and the evaluation of its toxicity profile in relation to other vinca alkaloids.

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PubMed1992

The anti-tumour effects of the prodrugs N-l-leucyl-doxorubicin and vinblastine-isoleucinate in human ovarian cancer xenografts.

N-l-leucyl-doxorubicin and vinblastine-isoleucinate can be considered as relatively non-toxic prodrugs from doxorubicin and vinblastine, respectively. A comparative analysis was carried out of the anti-tumour activity of the four compounds as well as vintriptol in four human ovarian cancer xenografts different in histology, growth rate and chemosensitivity. Injections were given i.v. weekly twice into mice bearing well-established s.c. tumours. At equitoxic doses, the amount of drug administered for N-l-leucyl-doxorubicin and vinblastine-isoleucinate was respectively 3-fold and 2-fold higher than the doses of the parent compound. N-l-leucyl-doxorubicin induced a growth inhibition > 50% in three out of four human ovarian cancer lines. The anti-tumour effects obtained were significantly better (P < 0.01) than in the case of doxorubicin. Vinblastine-isoleucinate studied in two of these lines could induce a growth inhibition of > 50%. This prodrug appeared slightly less effective than vinblastine. Insignificant growth inhibition (< 50%) was obtained by vintriptol.

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PubMed1992

Preclinical antitumour activity and animal toxicology studies of rhizoxin, a novel tubulin-interacting agent.

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1990

Macrophages and the activity of high endothelial venules. The effect of interferon-gamma.

Interruption of the afferent lymphatic vessels of rat popliteal lymph nodes led to the disappearance of the monoclonal antibody ED3-reactive subcapsular sinus macrophages within 3 weeks, but had no effect on the ED1+ macrophages in the paracortical area. This disconnection of the afferent lymph flow to the popliteal lymph node also reduced the capacity of high endothelial venules (HEV) to bind lymphocytes and led to a flattening of the HEV. Activating factors or cells in the incoming lymph might be responsible for the maintenance and function of several different cell populations and we therefore wished to determine if the effects of interruption could be restored by injection of recombinant rat interferon-gamma (rIFN-gamma). Injection of rIFN-gamma directly into operated lymph nodes could mediate an apparent increase of ED1+ cells within 24 h but rIFN-gamma could not restore the macrophage subpopulation in the subcapsular sinus, as recognized by monoclonal antibody ED3. Restoration of the decreased binding capacity of HEV could not be observed with the doses and time points tested, suggesting that HEV are a distinct type of endothelium.

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PubMed1990

Functional capacities of high endothelial venules appear not to be controlled by recirculating lymphocytes.

The influence of recirculating lymphocytes on the function and morphology of high endothelial venules (HEV) has been studied. Mice were depleted of lymphocytes by lethal (1200 cGy) total body irradiation; subsequently, the HEV in mesenteric and cervical lymph nodes were studied up to 7 days after irradiation for: 1) capacity to bind lymphocytes by using the in vitro HEV-binding assay, 2) for morphological aspects such as ultrastructure and endothelial height, 3) for presence of RNA (pyroninophylia) and MECA-325 expression. Although, commencing 3 days after irradiation, lymphocyte depletion was intense and no extravasation of lymphocytes was observed; HEV were capable of binding lymphocytes at normal levels. Also the ratio of B/T cell binding to HEV was comparable to normal. MECA-325 expression, pyroninophilia, and ultrastructure of high endothelial cells were not affected by lymphocyte depletion. However, the average height of endothelial cells, which is a measurement related to cell volume, declined during lymphocyte depletion, stabilizing at about 70% of normal levels from day 4. After intravenous injection of viable lymph node cells, endothelial cell height rapidly increased within a few hours in conjunction with lymphocyte extravasation and homing into the nodes. Restoration of endothelial cell height was not observed after infusion of thymocytes, lethally irradiated lymph node cells or supernatants rich in cytokines. We conclude that recirculating lymphocytes in blood and lymphoid tissues are not involved in controlling high endothelial cell activity including the specific function in lymphocyte extravasation. However, recirculating/extravasating lymphocytes contribute to the development of endothelial cell height. The significance of non-lymphoid (radioresistant) cells in the control of characteristic high endothelial function is suggested.

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PubMed1989

Anti-tumor and differentiation-inducing activity of N,N-dimethylformamide (DMF) in head-and-neck cancer xenografts.

The anti-tumor activity of the putative differentiation-inducing agent dimethylformamide (DMF) was assessed in 7 head-and-neck xenograft (HNX) lines transplanted into nude mice. The drug was administered intra-peritoneally at the maximum tolerated dose. A significant growth-inhibitory effect was observed in 3 out of 7 tumor lines tested. When compared with 5 conventional drugs active in patients with squamous-cell carcinoma of the head and neck (HNSCC), DMF was as effective as the most active drugs (cisplatin and bleomycin). The most sensitive xenograft line, the poorly differentiated tumor HNX-14C, was used to test the hypothesis that differentiation induction might play a role in the anti-tumor activity of DMF. Light microscopic examination did not show clear-cut alteration of differentiation characteristics such as keratin and keratin pearl formation. Furthermore, we used a monoclonal antibody to study the expression of cytokeratin 10 which is useful as a differentiation marker of human HNSCC tumors. Keratin 10, not present in HNX-14C tumors grown under control conditions, became expressed in some cells upon DMF treatment. Further evidence for a differentiation-inducing activity of DMF was found in electron-microscopic studies. In treated HNX-14C tumors, in addition to cells with normal ultrastructural features, better-differentiated cells were observed, as manifested by an increase in the number of tonofilaments and desmosomes. The results show that DMF has a potential value for the treatment of patients with head-and-neck cancer, and that differentiation induction might play a role in the anti-tumor action of the drug.

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PubMed1989

Interferon-gamma-increased adherence of lymphocytes to high endothelial venules.

Recirculating lymphocytes specifically adhere to and migrate through endothelium lining high endothelial venules (HEV), using specific and non-specific receptor-ligand systems. Interferons (IFN) profoundly affect the traffic of lymphocytes. Therefore the effects of interferon-gamma (IFN-gamma) on lymphocytes with respect to their interaction with HEV endothelium in lymph nodes were studied using the frozen section assay. In addition the organ-specificity of T- and B-lymphocyte adherence to HEV was investigated. Lymphocytes from spleen and peripheral lymph nodes showed increased binding to HEV of up to 35% compared to control lymphocytes after in vivo administration of IFN-gamma. The specificity of their binding did not change in terms of T:B-cell ratios. Increased adherence was also found by preincubation of lymphocytes with IFN-gamma in The enhanced binding was not due to increased expression of Mel-14 homing receptors and LFA-1 molecules on T and B lymphocytes, as shown by fluorescence-activated cell sorter analysis and antibody-blocking studies in the frozen section assay. Apparently IFN-gamma induces an additional Mel-14-independent and LFA-1-independent adhesion mechanism on lymphocytes.

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PubMed1987

Rapid decrease in lymphocyte adherence to high endothelial venules in lymph nodes deprived of afferent lymphatic vessels.

Occlusion of the afferent lymph flow to the lymph node (LN) results in both flattening of the endothelium of high endothelial venules (HEV) and a severe decrease in numbers of lymphocytes in transit across the walls of the flattened HEV. In the present study we have used the in vitro lymphocyte-binding assay to investigate the ability of HEV in rat LN to bind lymphocytes at various time points after occlusion of the afferent lymph flow. In addition the specificity of T and B lymphocyte adherence to HEV of such operated LN was studied. In normal LN, lymphocytes adhered to virtually all HEV using the in vitro binding assay. However, 1 and 2 weeks after operation lymphocytes bound to only 50-60% of the HEV and by 3-6 weeks 20-30%. The total numbers of lymphocytes bound to these HEV had also diminished to 10% of the control value 3-6 weeks after operation. Morphometric analysis showed that this was not only due to a reduction in the area of HEV endothelium available for lymphocyte adherence by flattening of the high endothelial cells, but also to a strong decrease in the numbers of bound lymphocytes per unit area high endothelium. In spite of the reduction in numbers of adhering lymphocytes the T/B cell ratio did not change. The results show that the reduction in lymphocyte binding of HEV in operated LN is a rapid event, probably due to loss of high endothelial cell determinants involved in binding of lymphocytes. The decrease in lymphocyte binding clearly precedes flattening of HEV endothelium suggesting that the height of high endothelial cells is of secondary importance to lymphocyte adherence.

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PubMed1986

Phagocytosis and lipofuscin accumulation in lymph node macrophages.

Lipofuscin is considered to be undigestible material present in secondary lysosomes. During histological and electron microscopical studies lipofuscin was observed in macrophages in popliteal lymph nodes in 3-6 month-old-male Wistar rats after occlusion of the afferent lymph flow to the lymph node. No pathological alterations were found in the lymph node after the operation. However, the number of macrophages was severely reduced. Simultaneously the number of secondary lysosomes increased in the remaining macrophages reaching a plateau 4 weeks after operation. At this time three quarters of the residual bodies already contained lipofuscin granules. In the following weeks almost all macrophages showed lipofuscin in increasing amounts. Macrophages in normal contralateral lymph nodes of the same rats rarely contained lipofuscin. The increased phagocytosis of the remaining macrophages thus preceded the appearance of lipofuscin. We suggest that lipofuscin results from an inadequate intralysosomal digestion.

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PubMed1984

Mesenteric lymph nodes: cells with surface and sytoplasmic immunoglobulins.

The distribution and morphology of cells with surface and cytoplasmic immunoglobulins were investigated in mesenteric lymph nodes (MLN) from rats, using both frozen and (fixed) paraffin sections, with a two-step immunoperoxidase technique. Anti-IgA, -IgE, -IgG and -IgM sera were used. Surface Ig-cells (sIg) of all four isotypes studied were found in MLN, mainly localized in the interfollicular area and within the follicle corona. The percentages of sIgA, IgE, IgG and IgM were about 15, 5, 45 and 35%, respectively. In addition, sIgM- and sIgG-cells were found around high endothelial venules. The percentages of cells containing IgA, IgG or IgM (cIg-cells) were about 60, 25 and 15%, respectively; only a few cIgE-cells were found. cIg-cells were not only present in the interfollicular areas and the medulla but also within the germinal centers of the follicles. These results are discussed with regard to the interaction between Peyer's patches (PP) and MLN.

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