Effects Of Biological Response Modifiers Research Articles

Automated laser scanning cytometry: A powerful tool for multi‐parameter analysis of drug‐induced apoptosis

Simultaneous analysis of multiple intracellular events is critical for assessing the effect of biological response modifiers, including the efficacy of chemotherapy. Here we used the automated laser scanning cytometry (LSC) for multi-parameter analysis of drug-induced tumor cell apoptosis. Using 2-mercaptopyridine-N-oxide-hydrate sodium salt, or the commonly used chemotherapeutic agents etoposide and camptothecin, we performed simultaneous analyses of apoptosis-related morphological features as well as fluorescence-based biochemical changes in a 96-well format. We demonstrate the scope of LSC as a platform for comparing multiple variables between different cell populations, distinguishing unique events at a single cell level within a sample population, and enabling simultaneous screenings in a single assay at multiple dosages and time-points. These data underscore the power of LSC for simultaneous multi-parameter analysis, which could have implications for screening or assessing the efficacy of drug responses in heterogeneous cell populations and at the single cell level.

Validation of the FACT-BRM with interferon-α treated melanoma patients

The somatic, neurocognitive, and psychiatric side effects of biological response modifiers (BRMs) have been documented in specific patient samples. Although these side effects likely have a predictable impact on patients quality of life (QOL), no instrument currently measures the cumulative effect of the various complaints patients' report. The current study investigated the reliability and validity of the Functional Assessment of Cancer Treatment-Biological Response Modifier (FACT-BRM) scale for measuring QOL in a sample of melanoma patients receiving interferon. Measures of distress, depression, and fatigue were also obtained using standardized, well-validated instruments. Results indicate increased symptom burden, depression, and fatigue, and decreased quality of life over 4 months of IFN therapy. The FACT-BRM demonstrated good psychometrics and sensitivity to change, and thus appears to be a good instrument for measuring QOL in patients receiving BRMs.

Potential role of NF-kB and RXR beta like proteins in interferon induced HLA class I and beta globin gene transcription in K562 erythroleukaemia cells.

Positive effects of biological response modifiers on cancer cells are usually measured using markers for increased immunogenicity as well as those for increased differentiation of the cells. An increase in levels of HLA class I antigens and the adult (beta) globin molecules are two such markers that may be used to assess the effect of modulators like interferons on the K562 erythroleukaemia cell line. Although interferon mediated up regulation of gene expression is thought to be primarily regulated by binding of proteins to the Interferon responsive cis elements in the promoters of IFN responsive genes, recent evidence has shown the induction of other transcriptional activators in response to IFN treatment. We present evidence for one such instance wherein up regulation of HLA class I and beta globin gene transcription are accompanied by induction of binding activities similar to RXR beta and kB proteins in K562 cells.

A New Endocrine Therapy Strategy for Bone Metastasis of Breast Cancer: The Effect of Biological Response Modifiers and 22-Oxacarcitriol on Animal Models.

To consider the treatment order of hormonal agents is very important in order to achieve a higher quality of life (QOL) and better survival rates in breast cancer patients with bone metastasis. Tamoxifen (TAM) or a luteinizing hormone-releasing hormone (LH-RH )analogue is the first-line, an LH-RH analogue (or TAM) the second-line, and medroxyprogesterone acetate(MPA) the third-line treatment in premenopausal patients with breast cancer. In postmenopausal patients, TAM (or toremifene) is the first-line, an aromatase inhibitor the second-line, and MPA the third-line treatment. In experimental studies using female Sprague-Dawley rats with 7, 12-dimethylbenz ma]anthracene (DMBA)-induced mammary carcinoma, biological response modifiers (BRM)(Krestin, Picibanil) and a vitamin D3 analogue, 22-oxacarcitriol (OCT)augmented the antitumor effect of hormonal agents. A combination of hormonal agents and BRM or OCT may be the endocrine therapy of choice for bone metastasis of breast cancer.

Former poison gas workers and cancer: incidence and inhibition of tumor formation by treatment with biological response modifier N-CWS.

Mustard gas is known to have mutagenic and carcinogenic effects on animal and human cells. In this report, 1,632 male Japanese who worked in poison gas factories at some time between the years 1927 and 1945 were studied to determine comparative risk for development of cancer, the reference population being data on Japanese males overall. The standardized mortality ratio (SMR) for lung cancer in workers directly and indirectly involved in the production of mustard gas was significantly elevated. In addition, SMR for lung cancer in worker who had worked for more than 5 years was also significantly elevated. Thus, poison gas workers who had engaged in the production of mustard gas or related work for more than 5 years are a high-risk group for lung cancer. Under the cancer preventive program, Nocardia rubra cell-wall skeleton (N-CWS) was administered to 146 former poison gas workers. During a 4.5 year observation period, development of cancers was found in 7 treated workers and 17 untreated controls. After elimination of the influence of smoking level, a significant suppression of development of cancers was noted in the N-CWS-treated workers as compared to the untreated controls. Although the molecular mechanisms of carcinogenesis in former poison gas workers remains unclear, our study proposes the possible effect of biological response modifiers in the prevention of cancer development in high-risk human subjects.

Role of macrophages in the immunotherapy of Lewis lung peritoneal carcinomatosis.

The underlying cellular mechanisms for the antitumor effects of biological response modifiers (BRMs) have not been clearly resolved. We have investigated this issue in the Lewis lung (3LL) peritoneal carcinomatosis model in which treatment with the BRM MVE-2 slows tumor growth and enhances survival. MVE-2 is a potent inducer of cytotoxic macrophages (m phi s); however, in the vivo tumoricidal properties of these m phi s remain to be firmly established. To directly establish that m phi s were at least in part responsible for the in vivo efficacy of MVE-2, a novel method of obtaining highly enriched m phi suspensions was developed which gave high purity, satisfactory yield, and excellent viability without affecting antitumor activity. Using the 3LL peritoneal carcinomatosis model and adoptive transfer techniques, we directly demonstrate that the majority of antitumor activity was associated with the adherent cell fraction enriched for m phi s. Histological observations supported this conclusion, indicating that MVE-2 treatment initially activated cells associated with nonspecific immunity, retarding tumor growth in the ascites long enough for a multifaceted immune response to develop.

Antitumor Effect of Intratumoral Administration of Biological Response Modifiers: Induction of Immunosuppressive Acidic Protein, a Type of α1‐Acid Glycoprotein, in Mice

The antitumor effects of biological response modifiers (BRMs) in an experimental mouse model, the “double grafted tumor system” were analyzed. Male BALB/c mice received simultaneous inoculations of Metn‐A fibrosarcoma cells on the right flank (106 cells) and left flank (2 × 105 cells) on day 0, and BRMs were injected intratumorally into the right tumor on days 3, 4 and 5. PSK (a protein‐bound polysaccharide preparation), interleuldn‐1 (IL‐1) and cepharanthin (R) cured not only the right, but also the left, non‐treated tumor in a double grafted tumor system. OK‐432 (a Streptococcus preparation) and BCG and tumor necrosis factor (TNF) cured the right tumor and inhibited the growth of the left tumor. Lentinan (a polysaccharide preparation) and IL‐6 inhibited neither the right nor the left tumor. Immunosuppressive acidic protein (IAP) in serum was increased transiently soon after intradermal injection of PSK, CR, OK‐432 and TNF in BALB/c mice. Lentinan, however, did not induce IAP. IAP in serum was gradually increased after intradermal inoculation of Meth‐A tumor in BALB/c mice. The biochemical difference between PSK‐induced IAP (early, inflammatory IAP) and Meth‐A‐induced IAP (late, tumor‐induced IAP) was investigated by crossed affinity immunoelectrophoresis with concanavalin A. IAP of murine serum was separated into 4 peaks. IAP in normal mouse was rich in high‐mannose type sugar chain (Peak 3) and contained no hybrid‐type sugar chain (Peak 4), which was present in inflammatory and tumor‐induced IAP. Inflammatory IAP was rich in biantennary sugar chain (Peak 2) and tumor‐induced IAP was rich in tri‐tetraantennary sugar chain (Peak 1).

Effect of biological response modifiers against pulmonary candidiasis in neutropenic mice

We investigated the prophylactic and therapeutic effects of biological response modifiers (rHG-CSF, M-CSF, rhIL-2) on pulmonary candidiasis in neutropenic mice. Cyclophosphamide treated mice were injected by the intratracheal route with 5 x 10(6) Candida yeast cells. Prophylactic treatment with rhG-CSF afforded significant protection against pulmonary candidiasis in neutropenic mice. Treatment with rhG-CSF also increased the number of peripheral blood neutrophils. The histopathological investigations in our experiments showed that the assembly of PMNs to the infected lung at 24 hrs after bacterial challenge was more remarkable in the rhG-CSF treated mice than that in the vehicle alone. Number of viable candida cells in the infected lung in the rhG-CSF treated mice were significantly decreased. The combination of rhG-CSF and fluconazole was more effective than those of each monotherapy. Prophylactic treatment with M-CSF or rhIL-2 had no influence on pulmonary candidiasis. These results show the possibility that rhG-CSF could be of help for treating human deep candidiasis not successfully treated with antimicrobial agents alone.

Enhancement of rat hepatic macrophages by treatment with interleukin-2 and streptococcal preparation OK432, with reference to antitumor activity, soluble factor production and Ia expression.

The effect of biological response modifiers, such as interleukin-2 (IL-2) and streptococcal preparation OK432, on the functions of hepatic macrophages was investigated. The macrophages, even with no exogenous stimulation, produced superoxide anion (O2-) and tumor necrosis factor (TNF), displayed cytotoxicity against K562 cells and cytostasis against P815 cells and expressed immune-region-associated antigen (Ia). IL-2 administered in vitro or in vivo enhanced O2- production by hepatic macrophages and the intravenous injection of OK432 also enhanced O2 production. Furthermore, IL-2 added to the culture medium of hepatic macrophages isolated from OK432-injected rats augmented O2- production even more. The TNF production and Ia expression of the macrophages were also increased by the intravenous injection of OK432. As with O2- production, the cytotoxicity of the cells was enhanced by OK432 injection or by IL-2 added to the culture medium and the combination of OK432 and IL-2 augmented their cytotoxicity even more. Thus, the present study suggested that IL-2 and OK432 induce the augmentation of the antitumor activity of hepatic macrophages, partly as a result of the increase in production of O2- and TNF and Ia expression.

ＬＡＫ細胞と標的細胞との接着性と，接着性に及ぼすＢＲＭ（Ｂｉｏｌｏｇｉｃａｌ Ｒｅｓｐｏｎｓｅ Ｍｏｄｉｆｉｅｒｓ）の影響について

ＬＡＫ細胞と標的細胞との接着性と，接着性に及ぼすＢＲＭ（Ｂｉｏｌｏｇｉｃａｌ Ｒｅｓｐｏｎｓｅ Ｍｏｄｉｆｉｅｒｓ）の影響について

Effects of biological response modifiers on childhood ALL being in remission after chemotherapy

Of 125 children with acute lymphoblastic leukemia (ALL), who had been in continuous remission for three years on chemotherapy, 108 patients received biological response modifiers (BRM) such as Bestatin, N-CWS, OK-432 and/or PSK in order to prevent relapse after treatment suspension. From 20 patients who were treated with PSK, 6 relapsed within 13 months. This relapse rate was quite similar to the rate observed with those children who were off therapy (4 relapses in 17 patients within 13 months). In contrast to these 37 patients, only 3 out of 31 patients who received Bestatin ( p < 0.05) and 8 out of 57 patients who received N-CWS or OK-432 relapsed. Based on these findings, BRMs used in the present study seems to be effective to prevent relapse of leukemia among childhood ALL who have electively stopped chemotherapy. Bestatin/biological response modifiers/ALL

Comparison of direct cytotoxic effects of biological response modifiers with their stimulative role on monocyte mediated tumor cell killing

Comparison of direct cytotoxic effects of biological response modifiers with their stimulative role on monocyte mediated tumor cell killing

Comparison of direct cytotoxic effects of biological response modifiers with their stimulative role on monocyte mediated tumor cell killing

Comparison of direct cytotoxic effects of biological response modifiers with their stimulative role on monocyte mediated tumor cell killing

Immune Status and Immune Therapy of Renal Cell Carcinoma

At present, no sufficient therapy for metastatic renal cell carcinoma is available. Several immunotherapeutical protocols have been studied, success rates, however, were inconsistent. The purpose of this study was to assess the pretherapeutic immunological status of 13 patients with metastatic and 16 patients with nonmetastatic renal cell carcinoma and of 15 healthy volunteers. Determined were differential blood counts, lymphocyte subpopulations, beta 2-microglobulin, tumor necrosis factor (TNF), neopterin, immunoglobulin, fibronectin and ferritin. Additionally, these parameters were recorded for monitoring an immunotherapeutical approach with the xenogeneic biological response modifier Keyhole limpet hemocyanine (KLH) in 10 patients with metastatic and in 5 patients with nonmetastatic disease. The pretherapeutic immunological status of patients with metastatic disease was characterized by significantly reduced T4-, T8- and B-cell counts. Significantly increased were granulocyte counts, beta 2-microglobulin, neopterin and TNF. In patients who did not suffer from metastases, only beta 2-microglobulin and neopterin were increased significantly. During immunotherapy, in patients with metastases, there was a decline of lymphocyte subsets and of the T4/T8-ratio, which correlated with progress of the disease. Humoral immune parameters showed no changes compared to pretherapeutic values. In patients who did not suffer from metastases, cellular immune parameters showed stable values during immunotherapy; neopterin, beta 2-microglobulin and TNF increased considerably. These findings indicate immunosuppression in patients with metastatic renal cell carcinoma, increasing with progression of the disease and possibly impairing the immunostimulating effects of biological response modifiers during immunotherapy. In conclusion, the clinical response of metastatic renal cell carcinoma to immunotherapy might be improved if the immunostimulant is combined with agents suitable to overcome immunosuppression, i.e. low doses of cyclophosphamide or inhibitors of prostaglandin synthesis. In addition, assessment of immune parameters for monitoring the actual immune status of a patient and the immunological effects of therapy was found to be a necessary part of immunotherapy.

Etiology of sepsis occurring in the immunocompromised host and its prevention. 2. Preventive effect of BRM to experimental Pseudomonas endogenous septicemia and analysis of its immunological etiology

In the former report, the bacterial portal of entry in experimental mice with bacteremia were analysed in detail. And it was clarified that almost all of the isolates from blood of cyclophosphamide (CY) and antibiotics treated mice were entered by their own flora, especially by their faecal flora. From this point of view, great care must be taken when using antibiotics for immunosuppressed patients, because it easily causes a super-infection, that is one of the most important factors of endogenous infections. In order to potentiate host immunity, we examined the preventative effect of biological response modifiers (BRM) to experimental endogenous septicemia. MDP-Lys (L18), rhG-CSF, and rhIL-1 were effective on experimental Pseudomonas aeruginosa endogenous septicemia of mice. The effect did not depend on the increased number of total leukocytes and PMN. Further experiments using nude mice suggested that the host defence mechanism inhibiting Pseudomonas endogenous infection might not depend on T-cell mediated immunity.

A mouse model for the study of blood-brain barrier permeability

This article describes a C57BL/6 mouse model for the investigation of blood-brain barrier (BBB) alteration. Osmotic modification of BBB was achieved by infusion of 1.6 M arabinose solution into the internal carotid artery with or without occlusion of the external carotid artery. BBB alteration was measured by infusing 2% Evans blue dye. Only 1.6 M arabinose-treated animals but not 0.9% NaCl controls displayed prominent ipsilateral staining of frontal and temporal lobes. Light blue staining occurred in animals sacrificed within 10 min after injection. Prominent staining occurred in animals sacrificed 1–6 hours later. Identically treated animals were maintained for up to 6 months without signs of systemic or neurological dysfunction. This model may permit study of the effects of biological response modifiers (BRMs) upon the central nervous system (CNS) in healthy and diseased mice.

Effects of biological response modifiers and cytotoxic drugs on the hCG secretion of term placental and choriocarcinoma cells

Effects of biological response modifiers and cytotoxic drugs on the hCG secretion of term placental and choriocarcinoma cells

1024 - Effects of Biological Response Modifiers on Metastatic Potential of the Dunning Prostate Tumor

1024 - Effects of Biological Response Modifiers on Metastatic Potential of the Dunning Prostate Tumor

The Effect of Biological Response Modifiers on Chronic and Latent Murine Cytomegalovirus Infections

Host-mediated antiviral effect of 2 biological response modifiers (BRM), OK-432, and PS-K, against murine cytomegalovirus (MCMV) was evaluated in chronically or latently infected mice. In the early stage of chronic MCMV infection, the BRM-induced resistance was evidenced by decrease in infectious viruses replicated in the salivary glands and by augmented cytotoxic activity of the spleen cells against YAC-1 cells and MCMV-infected mouse embryonic fibroblasts (MEF). In the late stage of chronic MCMV infection, the BRM treatment did not eliminate MCMV from the mice, but did prevent exacerbation of MCMV infection in the salivary glands induced by administration of cyclophosphamide (CY). In mice latently infected by MCMV, BRM treatment suppressed CY-induced reactivation of MCMV in the salivary glands. It was suggested that the antiviral effect of BRM against MCMV in chronically or latently infected mice was based on activation of natural killer (NK) cells and cytotoxic T lymphocytes (CTL).

Early Immunological Prediction of Renal Allograft Rejection

Reliable predictors of impending renal allograft rejection would be valuable for better patient management. To date, no available test has been shown to be consistently predictive and results have often been conflicting. We evaluated an effector of cell-mediated immunity, antibody-dependent cell-mediated cytotoxicity (ADCC) as well as the response of these cells to different biological response modifiers (BRM) in patients following renal allograft transplantation. The in vitro test used assayed monocytes as ADCC effector cells against antibody-sensitized chicken red blood cells. The effects of BRM were studied by preincubating the monocytes with lymphoblastoid IFN, recombinant alpha 2-interferon or gamma-interferon. A follow-up study was performed on 47 patients with end-stage renal disease treated with renal allograft transplantation. ADCC activity and its response to BRM were assayed prior to transplantation, 2, 4, and 9 weeks post transplantation. In the case of rejection, ADCC was then studied prior to initiation of antirejection therapy and for 2 months following treatment of rejection episode. We noted that in patients with stable grafts, the ADCC activity as well as its response to BRM declined gradually during the first 2 weeks post grafting and remained decreased up to 3 months after transplantation. In contrast, in recipients who experienced rejection episodes there was a sustained and significant increase in ADCC response to BRM during the first 3 weeks post grafting. By the time the diagnosis of rejection had been established the baseline ADCC activity had also increased. Following treatment and stabilization of the graft, ADCC activity and its response to BRM was decreased, similar to that in patients with stable grafts.(ABSTRACT TRUNCATED AT 250 WORDS)