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O Fodstad

Publications and source records attributed to O Fodstad.

At least 91 records · Page 5Linked to original sources
PubMed1993

[Transgenic mice as animal model of Cushing's syndrome].

Transgenic mice were generated with the polyoma early region promoter linked to cDNA encoding polyoma large T antigen (PyLT). Light microscopic examination showed up to 5 mm large pituitary adenomas in clinically ill transgenic mice. The tumour cells showed positive ACTH immuno-reactivity. The adrenal glands of clinically ill mice showed an increase in weight and exhibited medullary hyperplasia. These findings were unexpected, and might have been caused by transgene expression in the neuroendocrine cells of the adrenal medulla. Plasma ACTH measurements showed significantly increased levels in clinically ill PyLT-1 transgenic mice.

Adenoma↗
PubMed1993

Monoclonal antibody accumulation in experimental and spontaneous lung metastases of human malignant melanoma in rodents.

Monoclonal antibody (mAb) uptake in metastatic lung lesions was depicted and evaluated by digital autoradiography. The models examined were experimental metastases of a human melanoma in nude mice and spontaneous metastases of human melanoma in immunocompromised young rats. By comparing uptake patterns in local (s.c.) tumours and in lung processes of various sizes it was found that patterns were essentially similar in both types of malignant tissue. From the point of view of visualization, however, the high blood content of lung tissue resulted in high background and low contrast. This could be overcome by the use of rapidly cleared antibody fragments.

Animals↗
PubMed1993

Effective removal of SCLC cells from human bone marrow. Use of four monoclonal antibodies and immunomagnetic beads.

High dose chemotherapy with autologous bone marrow transplantation (ABMT) has shown promise in several types of cancer. There is, however, a risk of transfusing contaminating tumour cells with the bone marrow cells, e.g. in patients with small cell lung carcinoma (SCLC). To eliminate SCLC cells from normal human bone marrow, four monoclonal antibodies reactive with SCLC cells were used with immunomagnetic beads in model experiments. With two cycles of immunomagnetic elimination the individual antibodies removed 2.5-4.4 log of H-146 tumour cells from a single cell suspension, as assessed in a highly reproducible soft agar assay. Different combinations of two antibodies were only marginally more effective than the individual MAbs, whereas 5-6 log removal was obtained with a combination of all four antibodies. The method was equally effective when the tumour cells were mixed with bone marrow cells at a ratio of 1:10. The immunomagnetic procedure did not significantly affect the survival of normal progenitor cells, assessed in CFU-GM and CFU-GEMM assays. The results indicate that the procedure safely and effectively can be used to eliminate tumour cells from the bone marrow in conjunction with ABMT in patients with SCLC.

Antibodies, Monoclonal↗
PubMed1993

Rapid detection of transferrin receptor expression on glioma cell lines by using magnetic microspheres.

A rapid method for detecting the presence of transferrin receptors (TR) on human glioblastoma-derived cell lines is presented. The development of new treatment modalities, such as immunotoxins for central nervous system cancer, requires the identification of appropriate surface antigens on tumor cells. Seven established human glioblastoma-derived cell lines were assayed for the presence of TR with antibody-coated magnetic microspheres (immunobeads). The immunobeads bound to glioblastoma cells in the presence of human anti-TR monoclonal antibodies to a significantly greater degree than to control cell lines (P < 0.0001). The expression of TR was confirmed by standard immunocytochemical techniques. A 9L rat gliosarcoma cell line was used as a nonhuman control and did not demonstrate TR expression by either the immunobead assay or immunocytochemistry. This assay represents a simple, sensitive way to detect TR expression on malignant cells, which may be useful for the identification of other cell surface antigens that can be exploited by targeted therapies.

Brain Neoplasms↗
PubMed1993

Mapping of amplification units in the q13-14 region of chromosome 12 in human sarcomas: some amplica do not include MDM2.

Amplification of cellular oncogenes may be important for the development and progression of malignant tumors. In human sarcomas, amplification of several genes located to the q13-14 region of chromosome 12 has been reported. Because the mdm2 protein seems to inactivate the tumor suppressor protein p53, a selective growth advantage of 12q13-14 amplification has previously been assigned to increased copy number and expression of the MDM2 gene. We have analyzed a panel of 98 human sarcomas of different subtypes to characterize the 12q13-14 amplica and determine which of the genes GLI, A2MR, SAS, MDM2, and GADD153 (CHOP) in this region was most consistently amplified. MDM2 was amplified in 9 of the tumors, SAS in 10, GADD153 in 4, GLI in 2, and A2MR in 2. Amplification was, in most cases, associated with increased expression of the corresponding gene. SAS and MDM2 were coamplified in 8 of the tumors, whereas GADD153, GLI, and A2MR were only amplified together with SAS. One liposarcoma showed amplification of MDM2 alone, whereas two osteosarcomas and a rhabdomyosarcoma cell line showed amplification of SAS and GADD153 (CHOP) but not MDM2. It is suggested that the selective target for these amplica may be an as yet unidentified gene localized between SAS and MDM2.

Animals↗
PubMed1992

Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression.

Data obtained in experimental murine tumors and in clinical specimens of human breast cancer have suggested that the nm23 gene may function as a metastasis suppressor gene. In this report we examined the nm23 mRNA level in tumor tissue obtained from distant metastases in 33 patients with malignant melanoma. The gene was differentially expressed in the tumors with a 20-fold range in hybridization intensities. The levels of nm23 mRNA in benign nevi obtained from 12 of the 33 patients were relatively low, with a mean value of 17% of that in the melanomas. In attempts to relate the level of nm23 expression in the tumor metastases to progression of the disease, the time from biopsy of the primary tumor to the appearance of metastases was used as a clinical end point. It was found that patients developing metastases during the first 2 years after diagnosis had significantly lower levels of tumor nm23 expression (56% of the mean value) compared to patients with less aggressive disease (164%) (P < 0.0004). In concordance with previous data the association found here between low levels of nm23 mRNA and the malignant potential of melanomas suggests that the nm23 gene may be implicated in the mechanism of disease progression in some types of human cancer.

Chromosomes, Human, Pair 17↗
PubMed1992

Phase II preclinical drug screening in human tumor xenografts: a first European multicenter collaborative study.

In a European joint project carried out in 6 laboratories a disease-oriented program was set up consisting of a panel of 7 tumor types, each represented by 4 to 8 different human tumor lines, for secondary screening of promising anticancer drugs. Human tumor lines were selected on the basis of differences in histology, growth rate, and sensitivity to conventional cytostatic agents. Xenografts were grown s.c. in nude mice, and treatment was started when tumors reached a mean diameter of 6 mm in groups of mice where at least 6 tumors were evaluable. Drugs were given at the maximum tolerated dose. For evaluation of drug efficacy, median tumor growth curves were drawn, and specific growth delay and treated/control x 100% were calculated. Doxorubicin (8 mg/kg i.v. days 1 and 8) was effective (treated/control < 50%, and specific growth delay > 1.0) in 0 of 2 breast cancers, 1 of 3 colorectal cancers, 2 of 5 head and neck cancers, 3 of 6 non-small cell lung cancers, 4 of 6 small cell lung cancers, 0 of 3 melanomas, and 3 of 6 ovarian cancer lines. Amsacrine (8 mg/kg i.v. days 1 and 8) was not effective, while datelliptium (35 mg/kg i.p. days 1 and 8) was active against 2 of 6 small cell lung cancer lines. Brequinar sodium (50 mg/kg i.p. days 1-5) showed efficacy in 4 of 5 head and neck cancers, 5 of 8 non-small cell lung cancers, and 4 of 5 small cell lung cancer lines. The project has been shown to be a feasible approach. Clinical activity for doxorubicin and inactivity for amsacrine against solid tumor types was confirmed in the human tumor xenograft panel. Additional anticancer drugs will be studied in the European joint project to further define the reliability of this novel, promising screening approach.

Amsacrine↗
PubMed1992

Immunotoxins directed against the high-molecular-weight melanoma-associated antigen. Identification of potent antibody-toxin combinations.

To study factors influencing the cytotoxicity of immunotoxins (ITs), we compared the in vitro cytotoxicity of conjugates in which the plant toxin abrin and the bacterial toxin Pseudomonas exotoxin A (PE) were coupled by 2 different procedures to 2 MAbs, 9.2.27 and NR-ML-05, which bind to different epitopes on the melanoma-associated antigen p250. The individual target cell lines differed widely in sensitivity to the different ITs, as assessed by measurement of protein synthesis inhibition. The action of the ITs was highly specific, as the toxicity of abrin and PE conjugates was respectively 20-540 and 2,200-550,000 times higher in antigen-positive cell lines (FEMX, SESX, OHS) than in the antigen-negative line KPDX. The PE conjugates prepared with the 2 different MAbs differed in potency by factors of 16-126 in the target-cell lines, but were consistently more toxic than the abrin ITs. The results demonstrate that the cytotoxicity of ITs varies with the nature of both of its moieties and that optimal results require that toxins and MAbs be matched. Moreover, the 2 coupling procedures affected differentially the binding and potency of some ITs. Each of the 2 toxins was conjugated to a sheep anti-mouse antibody (SAM) and the toxicity of these 2 conjugates was tested in an indirect approach using 9.2.27 and NR-ML-05 as primary MAbs. The results showed that the indirect procedure would have correctly predicted the most potent antibody-toxin pair, indicating that the approach may be valid for selecting suitable combinations of MAbs and toxins for use as direct ITs.

ADP Ribose Transferases↗
PubMed1992

Site-dependent differences in sensitivity of LOX human melanoma tumors in nude rats to dacarbazine and mitozolomide, but not to doxorubicin and cisplatin.

Three model systems involving LOX human malignant melanoma cells in nude rats were used to compare the chemosensitivity of tumors growing in different tissues. Groups of 4-18 rats with either s.c. xenografts, lung tumor colonies, or bone metastases were treated with cisplatin, doxorubicin, dacarbazine, or mitozolomide. The antitumor effect in the s.c. model was expressed as specific growth delay, and in the experimental metastasis studies as relative increase in life span (RILS), calculated on the basis of observed disease-free survival. Cisplatin had a moderate but significant effect on the progression of LOX tumor growth in all three systems. Doxorubicin was clearly more efficacious, but for both drugs tumor-free survivors were rare or absent. Importantly, for each of the compounds the levels of response were roughly the same in all three models, with specific growth delay and RILS values in the range of 0.2-0.3 for cisplatin and 0.5-0.9 for doxorubicin. In contrast, a significant site-dependent difference in sensitivity of the LOX tumors was observed for two alkylating agents. Thus, dacarbazine, which temporarily caused complete regression of s.c. xenografts (specific growth delay = 21.0), showed a moderate activity in the lung tumor model (RILS = 1.0) but had only a limited effect (RILS = 0.4) on bone metastases. Mitozolomide gave a curative effect in 6 of 10 animals with s.c. and in 4 of 4 animals with lung tumors, whereas in the bone metastasis model it was only slightly superior to doxorubicin (RILS = 1.1). In preliminary attempts to elucidate the underlying mechanisms, no site-dependent differences in drug distribution and in two cellular detoxifying systems were detected. The data demonstrate the usefulness of the LOX models for studying the clinically relevant problem of site-dependent tumor response to chemotherapy.

Animals↗
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.

Animals↗
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)

Animals↗
PubMed1992

Immunotoxins and central nervous system neoplasia.

The poor prognosis associated with central nervous system (CNS) malignancy has led investigators to seek new, innovative treatment modalities. Immunotoxins, carrier molecules linked to toxic agents, combine high specificity for tumor-associated antigens with extreme potency. The rationale for both the development of these compounds and for their application to CNS neoplasia is explained. This report discusses the design and construction of immunoconjugates, using toxins that differ in their mechanism of action bound to ligands directed against various antigens. A comparison is made between the in vitro efficacy of standard chemotherapy and immunotoxins in glioblastoma- and medulloblastoma-derived cell lines. A review is included of the results of experiments in animals with leptomeningeal neoplasia, where prolongation of survival following intrathecal administration of immunotoxins has been reported. The obstacles encountered in clinical trials with other types of cancer are addressed and approaches to optimize the use of these novel agents in the context of treating malignant disease of the CNS are suggested.

Animals↗
PubMed1992

In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme.

The cytotoxic activity of immunotoxins constructed with human diferric transferrin (Tfn) as the carrier ligand and an abrin variant Pseudomonas exotoxin A (PE) and the diphtheria toxin mutant cross-reacting material (CRM) 107 as the toxin moieties were studied in vitro. Three malignant human cell lines, the glioblastomas multiforme SNB19 and SF295 and the LOX melanoma, and a nonhuman control murine melanoma cell line B16 were assessed. The presence of transferrin receptors on the cell lines was confirmed by direct 125I-Tfn binding assays. The 50% protein synthesis inhibitory concentration (IC50) values for all cell lines demonstrated that Tfn-abrin variant and Tfn-PE had comparable potency and were both more effective than Tfn-CRM 107. Monensin, a carboxylic ionophore, potentiated the effect of Tfn-abrin variant against glioma cells approximately 35-fold with IC50 values of 4.0 x 10(-13) M and 4.7 x 10(-12) M for SNB19 and SF295, respectively. Cytotoxic activity of Tfn-abrin variant (with or without monensin) and Tfn-PE was correlated with the degree of Tfn receptor expression measured on the cell lines. The exquisite in vitro cytotoxicity of Tfn-abrin variant and Tfn-PE immunotoxins against glioma and melanoma cells warrants further in vivo evaluation and future consideration of these agents for potential clinical application against glioblastoma multiforme and leptomeningeal neoplasia.

ADP Ribose Transferases↗
PubMed1992

Detection of bone marrow metastases in small cell lung cancer patients. Comparison of immunologic and morphologic methods.

An immunocytochemical method, involving four monoclonal antibodies (MAbs) previously selected for their specific binding to small cell lung cancer (SCLC) cells in human bone marrow, was used for detection of bone marrow metastases in 81 patients with diagnosed SCLC. This procedure was compared with two routine morphologic methods with regard to diagnostic efficiency and sensitivity. Bone marrow involvement was found in 26 patients (32%), one of which had limited disease according to conventional clinical criteria. Eight of the positive cases were exclusively diagnosed by immunocytochemistry, whereas the histologic and cytologic methods separately identified two patients each. Immunocytochemistry had a detection level of tumor cells in the mononuclear cell fraction of approximately 1-2%, whereas no patients with less than 10% immunocytologically detectable tumor cells were diagnosed by cytomorphologic examination of bone marrow aspirates. Evidence was obtained that the diagnostic efficiency of any method increased with the number of samples examined. Of the four MAbs used, the anti-NCAM antibody, MOC-1, labeled tumor cells in all immunologically positive patients, and in all but one of these patients all cytologically confirmed tumor cells were stained. The antibodies MOC-31, which recognize a cluster-2 antigen, and NrLu10 bound nearly all tumor cells in most cases, whereas MLuC1 only diagnosed tumor cells in a fraction of the patients. The results show that the immunocytochemical application of these antibodies is superior to morphologic techniques in detecting SCLC bone marrow metastases. Further use of the method might provide prognostically and therapeutically useful information.

Antibodies, Monoclonal↗
PubMed1992

An effective immunomagnetic method for bone marrow purging in T cell malignancies.

An immunomagnetic method was developed to purge human bone marrow of malignant T cells, for use in conjunction with autologous bone marrow transplantation in patients with acute lymphoblastic leukemia and lymphoma. Three monoclonal antibodies anti CD2 (BH1), CD5 (BB8) and CD7 (BF12) were used. In model experiments employing MOLT4 cells it was found that with 50-fold excess of immunobeads relative to antigen-positive cells, the use of each antibody alone resulted in a 3.3-3.6 log tumor cell depletion, as assessed in a sensitive and reproducible clonogenic soft agar assay. When all three antibodies were used in a mixture, a purging efficacy of 5 logs was achieved. Two treatment cycles improved these figures to about 4 logs and more than 5 logs. When MOLT4 cells were mixed 1:10 with fresh bone marrow cells the antibody mixture yielded 3.1 and more than 5 log tumor cell depletion with one and two treatment cycles, respectively. This procedure resulted in only an insignificant reduction of the number of CFU-GM and CFU-GEMM progenitor cells. In two patients autotransplanted with purged marrow, the loss of CFU-GM was 37% and 48%, and no tumor cells could be detected by immunocytochemistry after purging. Rapid and sustained engraftment was achieved and both patients remain in complete remission after more than 20 months.

Antibodies, Monoclonal↗
PubMed1991

Different metastasis patterns of a human melanoma cell line in nude mice and rats: influence of microenvironment.

The metastatic capacity of intravenously injected human FEMX-I melanoma cells in athymic nude mice and rats was compared. Young rats given 1 x 10(6) ascites tumor cells all died of lung tumors with a life span of 50 +/- 10 days (mean +/- SD). In contrast, in accordance with previous findings, only extrapulmonary metastases developed in mice. This host-dependent difference in metastasis pattern permitted studies on the role of factors that may influence the organ specificity of metastases. The tissue distribution of 125I-labeled FEMX-I cells did not differ in the two nude species during the first 12 hours after cell injection. The plating efficiency of FEMX-I cells in soft agar was increased by the addition of conditioned medium prepared from rat lungs, resulting also in a significant increase in colony size. In contrast, conditioned medium prepared from mouse lungs reduced the clonogenic capacity of the FEMX-I cells in a dose-dependent manner. Conditioned media prepared from rat and mouse liver, kidney, and spleen tissues either inhibited or had no effect on colony formation. The results suggest that the unexpected differential metastatic patterns observed in vivo may reflect differences in the presence of growth-modulating paracrine factors in the host lungs.

Animals↗
PubMed1991

Practical spontaneous metastasis model for in vivo therapeutic studies using a human melanoma.

In vivo studies aimed at therapy of spontaneous human tumor metastases have been hampered by the lack of practical experimental models. The LOX amelanotic melanoma model described here represents a transplantation model which rapidly and reproducibly results in spontaneous pulmonary metastasis following s.c. inoculation into athymic mice. Pulmonary lesions can be detected using a simple bioassay procedure which is useful for estimation of metastatic cell killing. Using this model we demonstrate that systemic therapy with cyclophosphamide or dacarbazine can produce metastatic cell killing consistent with complete eradication of established pulmonary metastases. This model may also prove useful for future experimental therapeutic studies aimed at prevention of metastases by manipulating tumor staging interval and treatment schedule.

Animals↗