Biomedical subjects

H Blomgren

Publications and source records attributed to H Blomgren.

At least 37 records · Page 2Linked to original sources

PubMed1991

Indomethacin modulation of monocyte cytokine release following pelvic irradiation for cancer.

Pelvic irradiation for urogenital cancer reduced monocyte release of tumour necrosis factor alpha (TNF-alpha). Addition of indomethacin to monocyte cultures increased TNF-alpha production after but not before irradiation. E. coli lipopolysaccharide (LPS) increased TNF-alpha release before as well as after radiation therapy and addition of indomethacin to LPS-stimulated monocytes further increased TNF-alpha production following radiotherapy. Spontaneous interleukin-1 (IL-1) release was increased in the cancer patients and was not significantly affected by radiation therapy. LPS increased IL-1 release before as well as after irradiation, but indomethacin did not further change IL-1 secretion. These findings suggest that prostaglandins differentially regulate TNF-alpha and IL-1 release. Administration of cyclo-oxygenase inhibitors during radiation therapy might increase TNF-alpha release in vivo and thereby enhance the host defence against tumours.

Aged↗

PubMed1991

Blood lymphocyte population following 131I treatment for hyperthyroidism.

A number of immunological parameters have been monitored for up to 6 weeks following 131I treatment for hyperthyroidism in Graves' disease. The aim was to examine whether this isotope treatment normalizes or further accentuates some immunological abnormalities which may be a manifestation of autoimmune reactions in these patients. It was confirmed that both the cellular composition and immunological reactivities of the patients' blood lymphocytes were abnormal before treatment. After 131I administration a slight lymphopenia occurred and the ratio between CD4 and CD8 positive T lymphocytes (helper-inducer/suppressor-cytotoxic), which was increased before treatment, increased further. Moreover, PWM-triggered IgM secretion in vitro was reduced by 50%. No other immunological parameters studied, such as secretion of other Ig classes, mitogenic responses of lymphocytes, and distribution of other lymphocyte subsets, changed to any detectable extent. It remains speculative whether the 131I-induced changes of the immune system may further accelerate the underlying autoimmune disease processes.

Adult↗

PubMed1991

Inhibition of tumor cell growth in vitro by 2-mercaptoethanesulfonate (mesna) and other thiols.

2-Mercaptoethanesulfonate (Mesna), which is used as a uroprotective agent during oxazaphosphorine treatment, was previously found to inhibit growth of several tumor cell lines in vitro. To test the possibility that this effect is due to the SH-group of mesna, other thiols have now been tested. It has been observed that L-cysteine, N-acetyl-L-cysteine and glutathione, on a molar basis, had effects similar to mesna on [3H]thymidine incorporations of several human tumor cell lines in vitro. The dose-response profiles were monophasic for some cell lines and biphasic for others. It is suggested that compounds with SH-groups, in relatively high concentrations, may be toxic for cells.

Cell Division↗

PubMed1990

Possible role of acrolein in oxazaphosphorine-induced enhancement of immunological reactivity.

The aim of the present study was to analyze further the immunopotentiating effects of low doses of oxazaphosphorines. We examined 4-hydroperoxycyclophosphamide (4-HC) and mafosfamide, which degrade spontaneously in water without requiring liver enzymes to become active. Both drugs, at concentrations ranging from 0.01 microM to 1 microM, enhanced mitogenic responses of human lymphocytes. Higher concentrations were toxic. Acrolein, which is one of the degradation products of oxazaphosphorines, had similar effects. Immunopotentiation was not monocyte-dependent. Attempts to inactivate released acrolein with human serum reduced toxicity but the immunostimulating property of the drugs remained Similar effects were noted when lymphocytes were exposed to acrolein dissolved in serum. 2-Mercaptoethane-sulfonate (mesna), which is highly reactive with acrolein, reduced the toxicity of solutions of both oxazaphosphorines and acrolein. Immunopotentiation was not clearly demonstrable since mesna itself enhanced the responses. Pretreatment of lymphocytes with 4-HC or mafosfamide did not reduce the capacity of concanavalin A to induce suppressor cells. It is speculated that acrolein may play a role in oxazaphosphorine-induced enhancements of immune responses.

Acrolein↗

PubMed1990

Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas.

Eight patients with malignant gliomas verified on CT scan, received an intravenous injection of 50 mg of Adriamycin R, 24 hours prior to surgical removal of the tumour. Peroperatively, both tumour and surrounding tissue specimens were obtained for determination of the tissue concentrations of Adriamycin and its reduced metabolite Adriamycinol. It was found that Adriamycin could be detected in tumour tissue from all patients. The concentration varied between 0.9 and 4.6 nmol/g tissue. In contrast, Adriamycin could only be detected in surrounding brain tissue from one patient. In an in vitro study a human malignant glioma cell line (U-251 MG) was exposed to various concentrations of Adriamycin for 24 hours. It was found that an intracellular drug concentration above 30 nmol/g cells caused a concentration dependent inhibition of cell growth. Thus, it is likely that the poor effect of Adriamycin on patients with malignant gliomas is due to an ineffective drug accumulation in the tumour tissue.

Adult↗

PubMed1990

In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer.

Radiation therapy triggers blood monocytes to an increased secretion of immunosuppressive prostaglandins (PGs), which in part can explain the post-irradiation impairment of lymphocyte blastogenesis. Since low mitogen responses of lymphocytes in irradiated breast cancer patients is linked to a poor prognosis a clinical trial is planned to examine if treatment with inhibitors of PG-synthesis during irradiation can counteract immunosuppression and increase survival. In the present investigation we have compared nine different inhibitors of PG-synthesis for capacity to enhance phytohemagglutinin responses of blood lymphocytes before and after irradiation for breast cancer. Five of the drugs (aspisol, indomethacin, meclofenamic acid, ketoprofen and diclofenac) enhanced the reactivity to more than 150%. In general, the strongest enhancements were observed in lymphocyte preparations obtained at completion of irradiation when reactivity was most depressed followed by those obtained at one month and before irradiation.

Adult↗

PubMed1990

Influence of RU 41.740 on human monocytes in vitro: release of soluble factors which retard multiplication of tumor cells in culture.

RU 41.740 (Biostim) is an immunostimulating substance of bacterial origin with a reported protective activity against bacterial infections in man. The aim of the present investigation was to determine if Biostim-exposed blood mononuclear cells release soluble factors in vitro which may inhibit growth of tumor cells in culture. It was observed that exposure of mononuclear cells to Biostim at concentrations as low as 1 ng/ml for 24 h resulted in the release of factors capable of retarding growth of K562 cells. Three human glioma cell lines tested also appeared to be sensitive whereas three other cell lines were less sensitive or resistant. The growth inhibitory factors were shown to be produced by monocytes which is in line with previous findings showing that Biostim is a potent activator of monocytes-macrophages. Biostim-exposed monocytes, however, did not express any cytotoxic activity for K562 cells using a short-term 51Cr-release assay. It is concluded that Biostim may trigger monocytes to release factors with anti-tumor activity. These factors have not yet been identified and it remains to be determined if their production increases during Biostim treatment and whether this is correlated to an anti-tumor activity in man.

Bacterial Proteins↗

PubMed1990

Changes of the blood lymphocyte population following 32P treatment for polycythemia vera.

Orally administrated Na2 32PO4 mainly accumulates in bone marrow where it emits beta-particles which may damage cells. Previously, we showed that 32P treatment for polycythemia vera (PVC) increased the phytohemagglutinin reactivity and proportions of T cells in the blood. Now we have examined the effects of 32P treatment for PCV on natural killer (NK) and B-lymphocyte subsets which are considered to undergo their maturation in bone marrow. A mean isotope dose of 240 MBq given to 14 patients reduced the peripheral lymphocyte counts to 60% at 6 weeks. B cells and NK cells were reduced to the highest relative extent followed by HNK-1 cells and T cells. Although the proportion of NK cells was reduced to 50% there was no concomitant reduction of NK activity against K562 cells. Pokeweed mitogen-triggered secretion of IgM was significantly reduced, but not that of IgG or IgA. It is suggested that lymphocytes which mature in bone marrow may be affected to the highest extent by 32P treatment in PCV.

Adult↗

PubMed1990

Anaplastic thyroid carcinoma. Doxorubicin, hyperfractionated radiotherapy and surgery.

Sixteen consecutive patients with anaplastic carcinoma of the thyroid were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin and debulking surgery. The radiotherapy was preoperatively administered to a target dose of 30 Gy in 3 weeks, and postoperatively to an additional dose of 16 Gy in 1.5 weeks. Radiotherapy was administered twice daily, 5 days a week, with a target dose of 1 Gy per fraction and with a minimum interval of 6 hours. A dose of 20 mg doxorubicin was administered intravenously 1 to 2 hours before the first radiotherapy session every week. Debulking surgery was feasible in 9 patients. Local complete remission was achieved in 5 patients and 3 of these are still alive disease-free at 10, 30, and 30 months respectively after diagnosis. Only 6 patients succumbed to a local failure. This combination regimen was well tolerated despite the patients' high age and advanced disease.

Aged↗

PubMed1990

Adjuvant bestatin (Ubenimex) treatment following full-dose local irradiation for bladder carcinoma.

The clinical value of adjuvant bestatin (Ubenimex) immunotherapy has been examined in a group of patients with urinary bladder cancer. Patients with non-metastatic transitional cell carcinoma of the bladder, scheduled for full-dose local irradiation therapy (64 Gy), were randomly allocated to adjuvant oral bestatin treatment (30 mg daily for at least 1 year), starting at completion of irradiation, or no bestatin. The trial included 194 evaluable patients with a follow-up period of 1.5-9.5 years. The overall survival of the two groups of patients did not differ statistically significantly (97 patients in each). Subgrouping of the patient material gave no evidence that the clinical efficacy of bestatin is related to sex, tumor category or malignancy grade.

Adjuvants, Immunologic↗

PubMed1990

Antitumor activity of 2-mercaptoethanesulfonate (mesna) in vitro.

2-Mercaptoethanesulfonate (mesna), which is used as an uroprotector during oxazaphosphorine therapy of cancer patients, was found to inhibit growth of several cultured human malignant cell lines in vitro. Dimesna, which is rapidly formed in the blood of mesna treated patients, had no effect and did not interfere with the growth inhibitory activity of mesna. For sensitive cell lines, complete growth inhibitions were usually observed at mesna concentrations of 10(-4) M. Higher concentrations were less toxic or even stimulated proliferation of some cell lines. There was no experimental evidence that the biphasic dose-response profiles were due to a more complete dimesna formation at high mesna concentrations. Since mesna, which is excreted in its monomeric form in urine, was reported to inhibit growth of superficial bladder cancer in patients, we examined the effects of repeated mesna administrations in cultures of bladder cancer cells. The results showed that this treatment caused growth inhibition of 2/4 "resistant" cell lines. The mechanisms by which mesna inhibits cell growth are unknown and it is not known if it acts selectively on malignant cells.

Animals↗

PubMed1989

Influence of low doses of an oxazaphosphorine on natural killer activity of human lymphocytes.

The influence of cis-4-sulfoethylthio-cyclophosphamide (mafosfamide) on natural killer cell activity was examined in vitro in order further to elucidate the possible immunological mechanisms of tumor regressions following low-dose oxazaphosphorine therapy. It was observed that cytotoxicity of human blood lymphoid cells was unchanged or reduced when the lymphocytes were pretreated for 24 h with mafosfamide or when the drug was present during incubation with K562 cells. However, when lymphoid cells were preincubated with human leukocyte interferon plus mafosfamide, natural killer activity was enhanced above the level caused by interferon alone. This enhancement was noted at mafosfamide concentrations of 1 nM-1 microM and was only present when the lymphocyte preparation was contaminated with monocytes.

Adjuvants, Immunologic↗

PubMed1989

Oral treatment with RU 41.740 (Biostim) in patients with advanced colorectal cancer: influence on the blood lymphocyte population.

Twelve patients with advanced colorectal carcinoma received oral treatment with RU 41.740, an immunomodulatory drug obtained from Klebsiella pneumoniae. The patients received three courses of RU 41.740, each consisting of 8 mg daily for 7 consecutive days, with free intervals of 3 weeks. This treatment did not significantly change the distribution of various lymphocyte subsets in the blood or the NK activity of the lymphocytes. However, PHA reactivity of purified lymphocytes increased significantly and exhibited a 2-3-fold enhancement 3 weeks after the last course. Such an increase was not observed in lymphocyte preparations which were not depleted of monocytes. It is concluded that 41.740 may be immunopharmacologically active in man when administered by the oral route.

Administration, Oral↗

PubMed1989

Immunosuppression in irradiated breast cancer patients: in vitro effect of cyclooxygenase inhibitors.

We have documented in previous studies that local irradiation therapy for breast cancer caused severe lymphopenia with reduction of both T and non-T lymphocytes. Non-T cells were relatively more depressed but recovered within six months. The recovery of T cells, on the other hand, remained incomplete 10-11 years after irradiation. Several lymphocyte functions were also severely impaired. An association was found between prognosis and postirradiation mitogen reactivity of lymphocytes from these patients. Mortality up to eight years after irradiation was significantly higher in patients with low postirradiation phytohemagglutinin and PPD reactivity. The radiation induced decrease in mitogenic response seemed mainly to be caused by immunosuppressive monocytes, which suggests that the underlying mechanism might be mediated by increased production of prostaglandins by monocytes. For this reason we examined the effect of some cyclooxygenase products on different lymphocyte functions and found that prostaglandins A2, D2, and E2 inhibited phytohemagglutinin response in vitro. Natural killer cell activity was also reduced by prostaglandins D2 and E2. The next step was to examine various inhibitors of cyclooxygenase in respect to their capacity to revert irradiation-induced suppression of in vitro mitogen response in lymphocytes from breast cancer patients. It was demonstrated that Diclofenac Na (Voltaren), Meclofenamic acid, Indomethacin, and lysin-mono-acetylsalicylate (Aspisol) could enhance mitogen responses both before and after radiation therapy. This effect was most pronounced at completion of irradiation. On a molar basis, Diclofenac Na was most effective followed by Indomethacin, Meclofenamic acid, and lysin-monoacetylsalicylate. The clinically beneficial effects of irradiation might be overshadowed by its effects on the immune system. If true, the value of treatment could be improved if radiation-induced suppression of lymphocyte response, which correlates inversely to survival, is reduced. Since such an effect can be achieved in these patients with cyclooxygenase inhibitors in vitro it is possible that it can be achieved also in vivo.

Breast Neoplasms↗

PubMed1989

Release of a votile factor from solutions of oxazaphosphorines which damage normal and malignant cells.

Oxazaphosphorines such as cyclophosphamide and ifosfamide must undergo hydroxylation at the carbon-4-atom of the oxazaphosphorine ring by liver enzymes before they spontaneously degrade to form the alkylating moiety. Some new oxazaphosphorines with different substitutions at the carbon-4-atom, however, undergo spontaneous hydrolysis when dissolved in water. Biological properties of these "activated" oxazaphosphophorines, which thus do not require biotransformation to liberate the alkylating moiety, have been studied extensively. We now demonstrate that the "activated" oxazaphosphorines, 4-(2-sulfonatoethylthio)-cyclophosphamide, 4-hydroperoxy-cyclophosphamide and 4-hydroperoxy-ifosfamide, present as aqueous solutions in wells of conventional microtest tissue culture plates release a votile factor which may penetrate into the media of neighboring cultures and strongly reduce their growth and viability. This phenomenon, which was temperature dependent, could be inhibited by cells or serum present in the drug solutions. Cyclophosphamide, ifosfamide or nitrogen mustard dissolved in water did not release detectable amounts of toxic factor. Acrolein, which is the only known votile metabolite of oxazaphosphorines, was also found to reduce cell growth in neighboring cultures, and its evaporation could be inhibited by cells and serum. It is concluded that the toxic votile factor, most likely acrolein, which is spontaneously released from certain oxazaphosphorines, may strongly affect cells in in vitro culture systems.

Animals↗

PubMed1988

Influence of adjuvant tamoxifen on blood lymphocytes.

The blood lymphocyte population was studied in 23 breast cancer patients treated with adjuvant tamoxifen for 1.5-2 years, and in an equal number of control patients. The size and cellular composition of the blood lymphocyte population, as assessed by monoclonal antibodies directed against various subsets, did not differ between the two patient groups. However, lymphocytes from the tamoxifen-treated patients exhibited a significantly lower NK activity against K562 cells. In contrast, the proliferative response of lymphocytes to ConA was significantly higher. These results indicate that tamoxifen may modulate the immune system.

Aged↗

PubMed1988

Human monocytes exposed to Biostim (RU 41740) alter lymphocyte mitogenesis: mechanisms of action.

The immunomodulatory agent RU 41740 (Biostim), which is derived from Klebsiella pneumoniae, may augment mitogenic responses of purified human blood lymphocytes. In non-purified preparations, however, responses may be sharply reduced due to the fact that Biostim induces monocytes to secrete immunosuppressive factors. This investigation has shown that both these biological activities can be exerted by a single, major glucoprotein fraction of Biostim termed F1. The Biostim-induced suppression of mitogen responses was not blocked by antibodies directed against IFN alpha or IFN gamma, thus speaking against IFN as being a mediator of suppression. Reduced suppression, however, was observed in the presence of drugs which inhibit arachidonic acid transformation. The cyclo-oxygenase inhibitors meclofenamic acid and indomethacin, which diminish biosynthesis of prostaglandins, could partially block the Biostim-induced suppression. Such an effect was not observed with 5,8,11-eicosatrynoic acid (ETI) which is an inhibitor of 12-lipoxygenase and leukotriene biosynthesis. Combinations of ETI and meclofenamic acid, however, were more potent than the latter tested separately. Another drug termed diclofenac Na, which apart from being an inhibitor of cyclo-oxygenase, rapidly clears cells of free arachidonic acid by binding to triglycerides, was found to be the most potent in preventing Biostim-induced suppression of mitogen responses. It is concluded that Biostim-exposed monocytes liberate increased amounts of immunosuppressive eicosanoids such as prostaglandins.

Adjuvants, Immunologic↗

PubMed1988

Changes of the blood lymphocyte subpopulations and their functions following 131I treatment for nodular goitre and 32P treatment for polycythemia vera.

The blood lymphocyte population was examined in 34 patients who were treated with 131I for toxic or atoxic nodular goitre. One to three doses of 300-550 MBq of 131I were administered at 1-week intervals. Lymphocyte counts were found to be significantly reduced at both 1 and 6 weeks after treatment. This decrease was accompanied by a changed composition of the lymphocyte subpopulations. The frequency of lymphocytes expressing membrane receptors for C'3 (EAC-rosette forming cells) was significantly reduced at 1 and 6 weeks following 131I administration. At 6 weeks there was a small but statistically significant increase of the frequency of T cells as identified by Leu 1 monoclonal antibodies. This was essentially due to an increased proportion of helper/inducer T cells as identified by Leu 3 monoclonals. 131I treatment also decreased the capacity of lymphocytes to secrete immunoglobulins (Ig) when stimulated with pokeweed mitogen (PWM). The greatest effect was observed for IgM. Secretion of IgG and IgA were less reduced. Mitogenic stimulations of lymphocytes with phytohemagglutinin (PHA) and concanavalin A were not significantly changed. It is concluded that these findings, with the exception of mitogen reactivity, are largely similar to those occurring following external radiation therapy for cancer. It is suggested that blood lymphocytes passing through the continuously irradiated gland are damaged mainly by beta-rays. The effect of 32P treatment on the blood lymphocyte population was examined in 16 patients with polycythemia vera. Before treatment the lymphocyte counts were within the normal range but the expression of certain membrane structures, as identified by monoclonal antibodies against total T cells (Leu 1 and 4), helper/inducer (Leu 3) and suppressor/cytotoxic T cells (Leu 2), were slightly decreased. Moreover, mitogenic responses of the lymphocytes to PHA and PWM-induced Ig secretion were impaired. Following a single oral dose of 32P (150-305 MBq), which normalized the production of erythrocytes and/or platelets, the blood lymphocyte counts were reduced by approximately 40 per cent 12 weeks after treatment. Examination of subsets demonstrated that the proportion of B-cells, as identified by B1 monoclonal antibodies, was decreased by the highest relative extent. On the other hand, lymphocytes expressing the above-mentioned T cell markers were somewhat increased. 32P treatment markedly increased PHA reactivity but it further reduced PWM-induced Ig secretion. The latter observation was in agreement with the finding that serum concentrations of Ig were reduced after treatment.

Aged↗