Sten Friberg

Endogenous nitric oxide counteracts antigen-induced bronchoconstriction

In anesthetized, artificially ventilated guinea pigs immunized against ovalbumin, challenge with aerosolized ovalbumin (0.1 mg) elicited a substantial and sustained increase of insufflation pressure. The inhibitor of endogenous nitric oxide (NO) synthesis, L-NAME (N omega-nitro-L-arginine methylester, 30 mg kg-1 i.v.), markedly augmented the response, the potentiation of which could be prevented by NO (20 p.p.m.) in the inhaled air. The results indicate an inhibitory effect of endogenous NO on antigen-induced bronchoconstriction.

Specific cytotoxicity by sensitized mouse thymus cells on tissue culture target cells

Specific in vitro cytotoxicity by mouse thymus cells on allogeneic tissue culture target cells was investigated employing a microassay. Lymph node and spleen cells from mice immunized against the target cells were highly active in the test, while thymus cells showed no appreciable effect. In contrast, a strong reactivity of thymus-derived cells was detected following intravenous transfer into irradiated allogeneic and F1 mice. This graft-versus-host immunization was detected by testing spleen cells from the host in an appropriate immune cell-target cell combination. The specific donor-versus-recipient direction of sensitization indicated that cells derived from the thymus were responsible for the effect. Moreover, the proportion of these reactive cells in the thymus was enriched by cortisone treatment of the donor animals. It is concluded that a population of lymphocytes in the thymus or their descendants which are relatively cortisone resistant and probably located in the medulla, are competent in mediating cellular immunity.

The promotion of patent airways and inhibition of antigen‐induced bronchial obstruction by endogenous nitric oxide

1 The aim of the present study was to investigate the role of nitric oxide (NO), histamine and leukotrienes in bronchial obstruction. For this, guinea‐pigs immunised against ovalbumin were studied under anaesthesia during challenge with antigen or agonists. 2 Challenge with nebulised antigen (0.1‐1 mg) elicited dose‐dependent increases in insufflation pressure which were abolished by combined administration of histamine and leukotriene antagonists. 3 Challenge with nebulised antigen (0.1‐1 mg) also elicited dose‐dependent increases in the concentration of endogenous nitric oxide in the exhaled air. After an initial peak, exhaled NO concentrations returned to pre‐challenge levels. 4 The increase in insufflation pressure and in exhaled NO caused by ovalbumin challenge was inhibited by combined administration of histamine and leukotriene antagonists. 5 In non‐immunised guinea‐pigs, challenge of the airways with nebulised histamine (10–1000 nmol) or leukotriene C4 (LTC4, 30–300 pmol) elicited dose‐dependent increases in insufflation pressure and in concentrations of endogenous NO in exhaled air. 6 The increase in exhaled NO correlated with the increase in insufflation pressure in response to ovalbumin, histamine and LTC4. An inhibitor of endogenous NO synthesis, Nω‐nitro‐l‐arginine methylester (l‐NAME, 30 mg kg−1 i.v.) abolished NO exhalation, and markedly augmented the airway responses to ovalbumin, histamine, or LTC4. 7 The potentiation by l‐NAME of the increase in insufflation pressure in response to ovalbumin or histamine was prevented by exogenous NO (20 p.p.m.) in the inhaled air. 8 The results indicate that endogenous NO has an inhibitory effect on bronchial obstruction. Increased NO release during allergen challenge is likely to be due to actions of histamine and leukotrienes.

Subcellular Localization Of Murine Histocompatibility Antigens In Tumor Cells: Localization of H-2 Antigens

SUMMARY Subcellular localization of murine histocompatibility antigens (H-2) was studied in the ascitic forms of the SEWA sarcoma (H-28 specificity), YAC lymphoma (H-2a), and the TA3/Stockholm and TA3/Hauschka (H-2a) carcinoma sublines. Live cells were radioiodinated specifically at their cell surfaces by the lactoperoxidase method and the protein-bound radioactivity was used as a quantitative marker for the cell membrane content at each subcellular fraction. The H-2 antigens were assayed quantitatively by cytotoxic inhibition tests. The results showed that the H-2 antigens are almost exclusively localized in the cell membrane. The TA3/Hauschka cells are characterized by a low expression of H-2 antigen sites available for antibody binding on the cell surface of intact cells. Following homogenization, however, all of the antigenic sites became available, reaching about one-third of the level characteristic for the fully antigenic TA3/Stockholm line. The H-2 antigen of the TA3/Hauschka cells was entirely restricted to the cell membranes as well, and it must be therefore concluded that its reactivity is impaired by the steric arrangement in the living cells.

Cancer Metastases: Early Dissemination and Late Recurrences.

BACKGROUND Metastatic cells from a primary tumor can occur before the primary cancer is detected. Metastatic cells can also remain in the patient for many years after removal of the primary tumor without proliferating. These dormant malignant cells can awaken and cause recurrent disease decades after the primary treatment. The purpose of this article is to review the clinical evidence for early dissemination and late recurrences in human malignant tumors. We used the following definitions: dormancy of cells may be defined as a nonproliferating state or an arrest in the cell cycle that results in a prolonged G0 phase. If one accepts the term “late metastases” to indicate a period exceeding 10 years from the removal of the primary tumor, then the two malignancies in which this occurs most frequently are cutaneous malignant melanoma (CMM) and renal cell carcinoma (RCC). METHODS PubMed, Web of Science, and Scopus were searched with the keywords “metastases,” “early dissemination,” “late recurrences,” “inadvertently transmitted cancer,” “tumor growth rate,” “dormancy,” “circulating tumor cells,” and “transplantation of cancer.” RESULTS Several case reports of early dissemination and late recurrences of various types of malignancies were found. Analyses of the growth rates of several malignant tumors in the original host indicated that the majority of cancers had metastasized years before they were detected. CMM, RCC, and malignant glioblastoma were the three most common malignancies resulting from an organ transplantation. CMM and RCC were also the two most common malignancies that showed dormancy. In several cases of transplanted CMM and RCC, the donor did not have any known malignancy or had had the malignancy removed so long ago that the donor was regarded as cured. CONCLUSION (1) Metastases can frequently exist prior to the detection of the primary tumor. (2) Metastatic cells may reside in organs in the original host that are not usually the site of detectable secondary tumors, for example, the kidneys and heart. (3) Metastatic cells remain dormant for decades after the primary tumor has been removed. (4) Dormancy might be reversible and lead to late recurrences.

Assessment of Concanavalin A reactivity to murine ascites tumours by inhibition of tumour cell migration

Abstract A method is described for semi-quantitation of the activity of the plant agglutinin Concanavalin A (Con A) with mammalian cells. The assessment is based on the inhibition of tumour cell migration by native Con A. This inhibition is directly proportional to concentrations of Con A from 1 to 50 μg/ml. We have studied the Con A binding capacity of cells by quantitative adsorption, with subsequent assessment of residual Con A activity in the supernatant by migration inhibition. Three different murine ascites tumours were used, one of which is not agglutinated by Con A. All three lines were found to bind Con A in similar amounts, and the calculated number of Con A receptors per unit of cell surface area was found to be close to previously reported data for cell lines maintained in vitro. The experimental results with tumour cell populations maintained in vivo support the view that there is no correlation between agglutinability of cells by Con A and the number of Con A receptors on the cell surface.

NANOMEDICINE: will it offer possibilities to overcome multiple drug resistance in cancer?

This review is written with the purpose to review the current nanomedicine literature and provide an outlook on the developments in utilizing nanoscale drug constructs in treatment of solid cancers as well as in the potential treatment of multi-drug resistant cancers. No specific design principles for this review have been utilized apart from our active choice to avoid results only based on in vitro studies. Few drugs based on nanotechnology have progressed to clinical trials, since most are based only on in vitro experiments which do not give the necessary data for the research to progress towards pre-clinical studies. The area of nanomedicine has indeed spark much attention and holds promise for improved future therapeutics in the treatment of solid cancers. However, despite much investment few targeted therapeutics have successfully progressed to early clinical trials, indicating yet again that the human body is complicated and that much more understanding of the fundamentals of receptor interactions, physics of nanomedical constructs and their circulation in the body is indeed needed. We believe that nanomedical therapeutics can allow for more efficient treatments of resistant cancers, and may well be a cornerstone for RNA based therapeutics in the future given their general need for shielding from the harsh environment in the blood stream.

Nanotechnology in the war against cancer: new arms against an old enemy – a clinical view

Clinical oncology is facing a paradigm shift. A new treatment philosophy is emerging and new targets are appearing that require new active agents. The medical use of nanotechnology - nanomedicine - holds several promising possibilities in the war against cancer. Some of these include: new formats for old drugs, that is, increasing efficacy while diminishing side effects; and new administration routes - that is, dermal, oral and pulmonary. In this overview, we describe some nanoparticles and their medical uses as well as highlight advantages of nanoparticles compared with conventional pharmaceuticals. We also point to some of the many technical challenges and potential risks with using nanotechnology for oncological applications.

Concanavalin A and Other Lectins in the Study of Tumor Cell Surface Organization

Cell surface structures of two mouse ascites tumors were studied using lectins. The tumors are sublines of the spontaneous mammary adenocarcinoma TA3 in strain A, differing in two main characteristics. Subline TA3-St grows only in syngeneic mice and has high expression of H-2 antigens. Subline TA3-Ha, in contrast, proliferates in all mouse strains, and has low amounts of exposed H-2 antigens. Concanavalin A (Con A), phytohemagglutinin (PHA) and Helix pomatia anti A hemagglutinin (HP) were used in agglutination tests, in binding experiments with 125I-labelled lectins and also in fluorescence studies with FITC-labelled lectins. Con A and PHA agglutinated the TA3-St cells but not the TA3-Ha cells. However, fluorescein-labelled Con A and PHA were bound to all cells (greater than 90%) of both sublines. Moreover both cell types contained an identical number of Con A receptors. The same result was obtained when the number of PHA receptors on the two sublines was compared. HP agglutinated TA3-Ha cells but not TA3-St cells. However, in this case, the difference in agglutinability between the lines was due to the presence or absence of HP receptors. All TA3-Ha cells contained large numbers of HP receptors. In contrast the majority (greater than 90%) of the TA3-St cells lacked HP receptors. (See article.) Trypsin released the HP receptors from TA3-Ha cells, at the same time making these cells agglutinable by both Con A and PHA. We conclude that the Ta3-Ha cells have a trypsin sensitive surface glycoprotein (or glycoproteins) detectable by HP, which is absent on most TA3-St cells. It is possible that this glycoprotein interferes with the agglutinability of TA3-Ha cells by Con A and PHA; whether it is also responsible for the low expression of H-2 alloantigen on this cell remains to be seen.

Peripheral nerves are sensitive to irradiation, Or: on the pitfalls from too short follow-up times.

Among radiotherapists, there has long-since existed an opinion that peripheral nerves were resistant to irradiation. In 1960, Clemedsen & Nelson [1], in their comprehensive review of the literature, state: ‘‘Nervous tissues, especially of adult animals, show a remarkable radio-resistance’’. Ordinary text-books in oncology and neurology, as a rule, have ignored the radiation-induced injuries of peripheral nerves, and also, the length of latency for late effects [2 12]. Not even such a specialized text-book as ‘‘Complications of Cancer Management’’ [13] published in 1994, present any information about radiationinduced injuries on peripheral nerves. This misconception about radiation and nerve injuries has been to the disadvantage of injured patients, since most medical doctors are not aware of the relationship between radiotherapy and nerve injuries. But there existed diverging information already prior to 1960. Janzen and Warren in 1941 [14], Linder in 1959 [15] irradiated the sciatic nerve of rats to a dose of 30 Gy in five days and found a focal nerve degeneration and scarring in 25% of cases when examined three to 11 months after irradiation. A later publication in 1961 [16] by Innes and Carsten reported that irradiation of the nerves of cauda equina of rats with a single dose of 35 Gy resulted in severe degenerative lesion in the nerves of all the animals after seven months. With today’s knowledge, radio-resistance of peripheral nerves can be regarded as a myth. There are at least three explanations to this myth: 1. Before the 1950s, low-energy machines were used. They had poor penetration in tissues, and did therefore not reach deep-seated nerves, 2. Lower irradiation doses were more frequent before 1950 than after, and 3. Patients were usually followed for a relatively short period of time, usually only five years. Nerve injuries may occur after longer latencies. Moreover, survival was considered to be the one and only major interest in some publications, whereas side effects such as injuries to peripheral nerves were disregarded (or not published). The sensitivity of the spinal cord to irradiation was known since Boden?s publication in 1948 [17], but the sensitivity of peripheral nerves at that time was not well-known. Boden described the latency for irradiation injuries to the spinal cord varied from five months to five years. It was not until Ware et al. [18], in 1975, had shown that nervous tissue was more sensitive to large fractions than other normal tissues and tumour cell populations. This is well illustrated by the numerous women injured by hypofractionated radiotherapy while treated for cancer of the breast. A review of the literature is presented below. The first clinical report of neuropathy to plexus brachialis (BPN) in humans came in 1964, when the Swiss neurologist Mumenthaler [19] published eight cases that had been irradiated after surgery for cancer of the breast. Some of these patients had been given very high doses, and one of them as much as 3 000 roentgen (28.5 Gy) to the axilla in a single