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Biomedical subjects

E Mihich

Publications and source records attributed to E Mihich.

At least 19 recordsLinked to original sources
PubMed2001

The twentieth international symposium of the Sapporo Cancer Seminar Foundation: gene environment interaction and cancer prevention.

The main goal of this Symposium was to discuss new information that could be used for the development of effective and novel approaches in cancer prevention. Mounting evidence indicates that genetic predisposition to cancer plays an important role in the etiology of the disease and that multistage carcinogenesis is for the most part based on multiple genetic changes, favoring cell survival. It is also evident that a variety of environmental factors lead to carcinogenic changes and determine cancer-causative or cancer-facilitative genetic changes; these factors may be endogenous in origin, as for example those that are endocrinologic in nature, or may come from the external environment, as for example products in tobacco smoke or in industrial pollution. It is therefore obvious that gene-environment interactions play a pivotal role in carcinogenesis and consequently may offer specific sites of intervention that may be useful for the development of cancer prevention. In general, cancer prevention can be implemented through Public Health measures, as is typically the case for intervention on smoking, industrial pollution, aflatoxin B contamination or, when we know more about it, dietary habits. On the other hand, it should become possible to design more rational chemoprevention and immunoprevention trials as more becomes known about the genetic changes predisposing to cancer and about the gene products that are responsible for the phenotypic changes leading to neoplasia.

Animals↗
PubMed2001

Expression, tissue distribution, and cellular localization of the antiapoptotic TIP-B1 protein.

TIP-B1 is a novel 27-kDa protein isolated from the cytosol of tumor necrosis factor (TNF)-stimulated cells. Cells preincubated with TIP-B1 are protected from TNF-induced apoptosis. This study showed that, as with normal fibroblasts and U937 histiocytic lymphoma, human MCF7 mammary adenocarcinoma cells were protected from TNF in a concentration-dependent manner by pretreatment with either TNF or purified TIP-B1. Immunoblot and immunohistochemical analyses indicated expression of both TIP-B1 mRNA and protein in MCF7 cells and heart, kidney, brain, liver, ovary, uterus, thymus, spleen, lymph node, and mammary gland cells throughout their development. Expression of TIP-B1 was heterogeneous, with staining of specific cell types within tissues. Based on the ability of TIP-B1 to protect both normal and tumor cells from TNF-induced apoptosis and its broad tissue distribution, with expression only in select cells within those tissues, a role for TIP-B1 in the regulation of TNF-induced effects is strongly indicated.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Twelfth annual Pezcoller symposium: signaling cross-talks in cancer cells.

Signaling as an overall cellular process is a prerequisite for the life of normal and cancer cells and is regulated by a multiplicity of mechanisms including "cross-talks" among pathways. Cross-talk is often critical in determining the decision of a cell to go toward a specific biological direction, such as proliferation, apoptosis, or differentiation. Both signaling pathways and cross-talk among them involve such biochemical processes as protein-to-protein interactions and well-regulated phosphorylation and dephosphorylation processes. This symposium was focused on mechanisms of the regulation of signaling with special emphasis on regulatory cross-talk among pathways and on changes that occur in cancer cells. The phenomena discussed were also considered with reference to opportunities that may be offered toward the development of potential therapeutic intervention.

Animals↗
PubMed2000

Protective specific immunity induced by doxorubicin plus TNF-alpha combination treatment of EL4 lymphoma-bearing C57BL/6 mice.

The therapeutic efficacy of a single (day 8), moderate dose (4 mg/kg, i.v.) of doxorubicin (DOX, Adriamycin) combined with recombinant human TNF-alpha (3 different doses and 5 different schedules, i.v.) was evaluated in C57BL/6 mice bearing an implant (s.c.) of the DOX-sensitive, TNF-alpha-resistant EL4 lymphoma. In parallel to monitoring survival, the levels of several host anti-tumor cytolytic effector functions of splenocytes and thymocytes were evaluated throughout the treatment period and in long-term survivors (LTS). DOX treatment alone resulted in a moderate (approx. 20%) increase in life span but no cures. TNF-alpha alone, at any tested dose or schedule, had little or no positive effect on survival. The combinations of DOX and TNF-alpha were only slightly better than DOX alone with respect to the time to death of mice that died (approx. 29% increase); however, each of the combinations involving 1,000 U TNF-alpha/injection produced a fraction (20% to 80%) of LTS. The host defense activities examined included those of splenic and thymic cytolytic T lymphocytes (CTL) and lymphokine-activated killer cells as well as splenic tumoricidal macrophages. Although most activities were modulated by tumor growth and/or treatment, only CTL responsiveness appeared to correlate with survival. CTL activity in the treated groups with LTS was significantly higher than in control groups late in the treatment period. Finally, ex vivo analyses of splenocytes and thymocytes together with the rejection of implanted tumor at 17 months established that LTS displayed specific long-term immune memory.

Age Factors↗
PubMed2000

A novel tumor necrosis factor-alpha inhibitory protein, TIP-B1.

TIP-B1, a novel TNF inhibitory protein, has been identified, purified and characterized from cytosolic extracts of TNF-treated human fibroblasts, and a partial TIP-B1 cDNA clone has been obtained. The (27 kDa pI approximately 4.5 TIP-B1 protein is unique based on both the sequence of three internal peptides (comprising 51 amino acids), and the nucleotide sequence of the corresponding cDNA clone. TNF-sensitive cells, when exposed to TIP-B1 prior to the addition of TNF, are completely protected from TNF-induced lysis. Thus, this TIP-B1 treatment effectively makes these cells TNF-resistant. Furthermore, TIP-B1 protects cells from apoptotic lysis induced by TNF. TIP-B1 does not interfere with the interactions between TNF and the TNF receptors based on flow cytometric analysis of the cellular binding of biotinylated TNF. These and other data indicate that TIP-B1 is not a soluble TNF receptor, nor an anti-TNF antibody, nor a protease that degrades TNF, yet TIP-B1 functions when added exogenously to cells. Thus, TIP-B1 is not one of the proteins previously reported to be involved in resistance to TNF. The fact that incubation of the newly discovered novel TIP-B1 with TNF-sensitive cells protects them from TNF-induced cell death, including TNF-mediated apoptosis, makes TIP-B1 a candidate for therapeutic modulation of TNF-induced effects.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Anticancer drugs plus cytokines: immunodulation based therapies of mouse tumors.

As demonstrated in this laboratory, several cytotoxic anticancer agents have immunomodulating effects at relatively low doses and, in combination with non-toxic doses of certain cytokines, can exert immunity-dependent curative effects in mouse tumor models. Thus, adriamycin (Dox) has been shown to enhance the activation of macrophages with associated increases of IL1 and TNF production, to stimulate the production of IL2 and the development and action of CTLs. In the EL4 lymphoma C57BL/6 mouse model, combinations of appropriate regimens of Dox plus IL2 or TNF induce cures and the long-term survivors exhibit life-long immunological memory. Combinations of cyclophosphamide plus TNF have analogous effects. In the E0771 breast tumor C57BL/6 mouse model, Dox plus TNF at doses which are without antitumor activity when given alone, cause complete cures of established tumors with concomitant stimulation of CTL and NK cells responses. The mechanisms involved in these therapeutic responses are discussed. In conclusion, the results obtained substantiate the possibility of establishing antitumor curative combination regimens based on the utilization of low non-toxic immunomodulating doses of certain anticancer drugs and specific cytokines.

Adjuvants, Immunologic↗
PubMed2000

New leads in cancer therapeutics: a keynote address.

The main problems in cancer chemotherapy are related to the fact that the available drugs are not specific nor selective enough in their anticancer action. Therefore, even a low degree of resistance at the target tumor level is sufficient to impart clinical resistance because the dose of drug cannot be increased sufficiently to overcome it without incurring unacceptable toxicity. In the face of the above mentioned difficulties, several directions of research are being currently pursued towards developing more effective and selective treatments of cancer. These include: 1) continuing traditional approaches of drug discovery stemming from lead chemical structures and in many cases utilizing combinational chemistry followed by suitable screening efforts; 2) Increasing the antitumor effectiveness of available drugs through: a) making it possible to increase drug dose intensity by protecting normal tissues from limiting toxicity through genetic manipulation or combination with such agents as GM-CSF or IL15; b) attempting to increase the specificity of drug delivery through the administration of agents encapsulated in suitable liposome or conjugated with appropriate antibodies or cytokines; c) increasing the sensitivity of target tumor to a drug by specific metabolic modulations as it was done, for example, in the case of combinations of fluoropyrimidines with leukovorin; 3) counteracting resistance to drugs through genetic and/or epigenetic approaches aimed at modifying, for example, mechanisms of drug uptake or retention or at reducing anti-apoptotic mechanisms; 4) attempting to improve biotherapeutic treatments, for example, utilizing novel therapeutic vaccines or antibodies, or treatments based on intervention on angiogenesis or on intercellular or cell-matrix relationships; 5) continuing efforts to develop more effective and selective combination treatments with drugs, biologicals or different modalities; and, 6) developing new treatments based on intervention at novel molecular targets which have an essential role in the physio-pathology of the cancer cell. The latter approach is the main subject of this address.

Animals↗
PubMed1999

Identification, characterization, and cloning of TIP-B1, a novel protein inhibitor of tumor necrosis factor-induced lysis.

Some cancer cells evade elimination by virtue of their insensitivity to agents that induce apoptosis. Conversely, the side effects of anticancer agents could be diminished if normal cells were more resistant. To further elucidate the factors that contribute to the susceptibility of a cell to apoptosis, these investigations were designed to identify proteins isolated from cells exposed to low concentrations of tumor necrosis factor (TNF) that, when incubated with normally TNF-sensitive cells, protect these cells from TNF-induced cytotoxicity. TIP-B1, a novel protein, has been identified, purified, and characterized from cytosolic extracts of TNF-treated human fibroblasts. The approximately 27 kDa pI-4.5 TIP-B1 protein is unique based on both the sequence of three internal peptides (comprising 51 amino acids) and the nucleotide sequence of the corresponding 783-bp cDNA partial clone. Western blot analyses using polyclonal antisera raised against both the purified native TIP-B1 and the approximately 14 kDa product of the cDNA partial TIP-B1 clone, as well as Northern blot analyses using the cDNA insert as a probe, indicate that TIP-B1 may belong to a family of proteins that are expressed in a number of cell lines from diverse tissues. TNF-sensitive cells, when exposed to 4-10 microg/ml concentrations of TIP-B1 prior to the addition of TNF, are completely protected from TNF-induced lysis. Furthermore, TIP-B1 protects cells from apoptotic lysis induced by TNF. Preincubation of TIP-B1 with TNF does not affect the ability of TNF to induce lysis. Moreover, TIP-B1 does not seem to interfere with the interactions between TNF and the TNF receptors, based on a preliminary flow cytometric analysis of the cellular binding of biotinylated TNF. On the basis of these characteristics, TIP-B1 is not a soluble TNF receptor, an anti-TNF antibody, nor a protease that degrades TNF; yet TIP-B1 functions when added exogenously to cells. These characteristics, its novel sequence, and its function when added exogenously to cells indicate that TIP-B1 is unique and is not one of the other proteins reported previously to be involved in resistance to TNF. The ability of TIP-B1 to function after exogenous incubation with target cells makes TIP-B1 a likely candidate for therapeutic manipulation of TNF-induced effects.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Thymic anti-tumor effectors in mice cured of lymphoma by cyclophosphamide plus TNF-alpha therapy: phenotypic and functional characterization up to 20 months after initial tumor inoculation.

As reported previously, cyclophosphamide plus tumor necrosis factor-alpha treatment of C57BL/6 mice bearing advanced EL4 lymphoma induced approx. 60% long-term (i.e., >60 days) survivors. These mice developed protective immunity, as evidenced by 1) rejection (100% survival) of EL4 tumor re-implanted on day 60 (day 0 = initial tumor implantation); and 2) development of significant levels of specific EL4 tumor cell killing activity by both splenocytes and thymocytes. Using this model, age-related changes in functionally and phenotypically definable thymocyte subsets were assessed. In thymocytes from 90 to 308 day survivors, specific immune memory was long term; both CD4+ and CD8+ cells were required for the ex vivo stimulation of lytic activity, but the specific anti-EL4 cytotoxic effector was CD4-CD8+. On day 520, the surviving mice were randomized into 2 groups. One group received a second re-challenge with EL4 tumor cells and all survived. The other group was sacrificed on day 520. Their thymocytes, exposed to X-irradiated EL4, developed anti-EL4 lytic activity and, in comparison with thymocytes of young and age-matched control mice, were markedly enriched in CD4-CD8+CD44+ cells. On day 625, thymocytes from the survivors of the day 520 re-challenge were evaluated and were found to have developed specific anti-EL4 lytic activity. Phenotypically, they had returned toward the pattern seen in age-matched control mice although CD4-CD8+CD44+ cells remained increased. These mice were > or = 2 years old, the median life span of C57BL/6 mice. Thus, mice cured of tumor by an immuno-modulating regimen rejected re-implanted primary tumor and maintained specific thymic anti-tumor immune memory for life.

Animals↗