thymosin and Neoplasms

Prothymosin alpha (proTα) is a ubiquitous polypeptide first isolated by Haritos in 1984, whose role still remains partly elusive. We know that proTα acts both, intracellularly, as an anti-apoptotic and proliferation mediator, and extracellularly, as a biologic response modifier mediating immune responses similarly to molecules termed as "alarmins". Our research team pioneered the elucidation of the mechanisms underlying the observed activities of proTα.. We were the first to demonstrate that proTα levels increase during normal and abnormal cell proliferation. We showed that proTα acts pleiotropically, inducing immunomodulatory effects on immune cell populations. We revealed that the immunoreactive region of proTα is the carboxyterminal decapeptide proTα(100-109) and both molecules stimulate innate immune responses, signaling through Toll-like receptors (TLRs), specifically TLR-4. We reported that proTα and proTα(100-109) bind on the surface of human neutrophils on sites involving TLR-4, and cell activation is complemented by cytoplasmic calcium ion influx. Further, we showed that proTα and proTα(100-109) act as adjuvants upstream of lymphocyte stimulation and, in the presence of antigen, promote the expansion of antigen-reactive effectors. Most recently, we reported that proTα(100-109) may accumulate in experimentally inflamed sites and can serve as a surrogate biomarker in severe bacterial infections, proposing that extracellular release of proTα or proTα(100- 109) alerts the immune system during conditions of danger.. We, therefore, suggest that proTα, and likely proTα(100-109), act as alarmins, being important immune mediators as well as biomarkers, and could eventually become targets for new therapeutic/diagnostic approaches in immune-related diseases like cancer, inflammation, and sepsis.

Topics: Alarmins; Autoimmune Diseases; Humans; Immunity, Innate; Killer Cells, Natural; Neoplasms; Protein Precursors; Sepsis; T-Lymphocytes; Thymosin; Toll-Like Receptors

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines. Due to the immune stimulating effects of Ta1, the compound would be expected to show utility for treatment of immune suppression, whether related to aging or to diseases such as infection or cancer. Extensive studies in both the preclinical and clinical setting will be summarized in the subsequent sections. These studies have demonstrated improvements in immune system cell subsets and the potential of Ta1 for the treatment of a range of diseases.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Disease Models, Animal; Humans; Immunity; Immunologic Deficiency Syndromes; Immunosuppression Therapy; Infections; Mice; Neoplasms; Thymalfasin; Thymosin; Vaccines

The thymus gland produces soluble molecules, which mediate significant immune functions. The first biologically active thymic extract was thymosin fraction V, the fractionation of which led to the isolation of a series of immunoactive polypeptides, including prothymosin alpha (proTα). ProTα displays a dual role, intracellularly as a survival and proliferation mediator and extracellularly as a biological response modifier. Accordingly, inside the cell, proTα is implicated in crucial intracellular circuits and may serve as a surrogate tumor biomarker, but when found outside the cell, it could be used as a therapeutic agent for treating immune system deficiencies. In fact, proTα possesses pleiotropic adjuvant activity and a series of immunomodulatory effects (eg, anticancer, antiviral, neuroprotective, cardioprotective). Moreover, several reports suggest that the variable activity of proTα might be exerted through different parts of the molecule. We first reported that the main immunoactive region of proTα is the carboxy-terminal decapeptide proTα(100-109). In conjunction with data from others, we also revealed that proTα and proTα(100-109) signal through Toll-like receptor 4. Although their precise molecular mechanism of action is yet not fully elucidated, proTα and proTα(100-109) are viewed as candidate adjuvants for cancer immunotherapy. Here, we present a historical overview on the discovery and isolation of thymosins with emphasis on proTα and data on some immune-related new activities of the polypeptide and smaller immunostimulatory peptides thereof. Finally, we propose a compiled scenario on proTα's mode of action, which could eventually contribute to its clinical application.

Topics: Adjuvants, Immunologic; Humans; Immunity; Molecular Structure; Neoplasms; Neuroprotective Agents; Peptide Fragments; Protein Precursors; Thymosin; Virus Diseases

Toll-like receptor (TLR) agonists possess remarkable properties, particularly with regard to dendritic cell activation, promoting Th1-type cytokine production and optimizing cytotoxic T-cell responses. Preclinical and clinical studies conducted to date show that TLR agonists can improve currently applied anticancer vaccination protocols. Although these have resulted in the US FDA approval of three TLR agonists for use in humans, their abundant application encounters limitations, principally due to dose-limiting toxicity evoking from systemic cytokine production. Here, using selected examples of clinical studies, we provide a concise review regarding the knowledge acquired thus far on the adjuvant use of TLR agonists as cancer vaccine components. We also provide evidence on the exploitation of a novel TLR agonist, prothymosin-α, which enhances the efficacy of tumor-reactive effectors without causing severe adverse effects.

Topics: Adjuvants, Immunologic; Animals; Cancer Vaccines; Clinical Trials as Topic; Humans; Immunotherapy; Neoplasms; Protein Precursors; Rats; Thymosin; Toll-Like Receptors; Treatment Outcome

β-thymosins, including thymosin β4 (Tβ4), Tβ10, and Tβ15, are a family of highly conserved 5 kDa peptides. They are involved not only in normal cell migration, but also in tumor metastasis. However, the molecular mechanisms of β-thymosins to regulate cell migration and other functions are not fully understood. Recently, this important area is under active investigation worldwide. Many new discoveries have been made from molecular biology and cell culture models as well as animal models and human diseases. This timely review provides the most updated information about functional roles and molecular mechanisms of β-thymosins in normal tissues and disease conditions.

Topics: Actins; Animals; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Neoplasm Metastasis; Neoplasms; Thymosin

The thymus is a central lymphoid organ with crucial role in generating T cells and maintaining homeostasis of the immune system. More than 30 peptides, initially referred to as "thymic hormones," are produced by this gland. Although the majority of them have not been proven to be thymus-specific, thymic peptides comprise an effective group of regulators, mediating important immune functions. Thymosin fraction five (TFV) was the first thymic extract shown to stimulate lymphocyte proliferation and differentiation. Subsequent fractionation of TFV led to the isolation and characterization of a series of immunoactive peptides/polypeptides, members of the thymosin family. Extensive research on prothymosin α (proTα) and thymosin α1 (Tα1) showed that they are of clinical significance and potential medical use. They may serve as molecular markers for cancer prognosis and/or as therapeutic agents for treating immunodeficiencies, autoimmune diseases and malignancies. Although the molecular mechanisms underlying their effect are yet not fully elucidated, proTα and Tα1 could be considered as candidates for cancer immunotherapy. In this review, we will focus in principle on the eventual clinical utility of proTα, both as a tumor biomarker and in triggering anticancer immune responses. Considering the experience acquired via the use of Tα1 to treat cancer patients, we will also discuss potential approaches for the future introduction of proTα into the clinical setting.

Topics: Animals; Biomarkers, Tumor; Humans; Immunotherapy; Neoplasms; Protein Precursors; Thymosin

Since it was first identified, thymosin alpha 1 (Tα1) has been characterized to have pleiotropic effects on several pathological conditions, in particular as a modulator of immune response and inflammation. Several properties exerted by Tα1 may be attributable to a direct action on lymphoid cells. Tα1 has been shown to exert an immune modulatory activity on both T cell and natural killer cell maturation and to have an effect on functions of mature lymphocytes, including stimulating cytokine production and cytotoxic T lymphocyte-mediated cytotoxic responses. In previous studies we have shown that Tα1 increases the expression of major histocompatibility complex class I surface molecules in murine and human tumor cell lines and in primary cultures of human macrophages. In the present paper, we describe preliminary data indicating that Tα1 is also capable of increasing the expression of tumor antigens in both experimental and human tumor cell lines. This effect, which is exerted at the level of the target tumor cells, represents an additional factor increasing the antitumor activity of Tα1.

Topics: Antigens, Neoplasm; Cell Line, Tumor; Humans; Immunologic Factors; Killer Cells, Natural; Neoplasms; T-Lymphocytes; Thymalfasin; Thymosin

Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour cells and to resist infections due to immunosuppression induced by the disease and antineoplastic therapy.. To evaluate the effectiveness of pTE and sTP for the management of cancer.. We searched CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE, EMBASE, AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, HEALTHSTAR, HTA, SOMED and LILACS (to February 2010).. Randomised trials of pTE or sTP in addition to chemotherapy or radiotherapy, or both, compared to the same regimen with placebo or no additional treatment in adult cancer patients.. Two authors independently extracted data from published trials. We derived odds ratios (OR) from overall survival (OS) and disease-free survival (DFS) rates, tumour response (TR) rates, and rates of adverse effects (AE) related to antineoplastic treatments. We used a random-effects model for meta-analysis.. We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin α(1)). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10  for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin α(1) the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I² = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23,  P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias.. Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin α(1), there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy.

Topics: Adjuvants, Immunologic; Adult; Disease-Free Survival; Female; Humans; Immune System; Immunocompromised Host; Male; Neoplasms; Peptides; Thymalfasin; Thymopentin; Thymosin; Thymus Extracts; Thymus Gland

The natural tetrapeptide acetyl-ser-asp-lys-pro (AcSDKP) is formed in vivo by enzymatic cleavage of the N terminus of thymosin beta4 by prolyl oligopeptidase (POP). Recently, AcSDKP was shown to promote angiogenesis. Because of the critical role of neovascularization in cancer development, the levels of AcSDKP and POP activity in a number of different malignant tissues were investigated. Our studies revealed that AcSDKP levels were markedly elevated in neoplastic diseases including hematologic malignancies and solid neoplasms. Consistent with this finding, the enhanced activity of POP was also detected in all analyzed specimens of cancer tissues. Both these novel findings are in concert with the previously reported overexpression of thymosin beta4 in a large variety of malignant tumors and with its potential role in cancerogenesis. The physiological relevance of these findings awaits further studies; however, our first results strongly suggest a key role for AcSDKP in the pathogenesis of cancer.

Topics: Animals; Biochemical Phenomena; Dipeptides; Mice; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Prolyl Oligopeptidases; Serine Endopeptidases; Thymosin

Aberrant expression of thymosin beta4 (Tbeta4) has recently been found to be associated with colorectal carcinoma (CRC) progression evidently due to an increase of the motility and invasion of tumor cells and the induction of a proangiogenic phenotype of endothelial cells. Both mechanisms depend upon matrix-degrading proteases, particularly plasmin and matrix metalloproteinases (MMPs) that are responsible for extensive tissue remodeling. Cleavage of ECM macromolecules weakens the structural integrity of tissues and exposes cryptic domains of extracellular components, which elicit biological responses distinct from intact molecules. Interestingly, signaling via integrins (alphaVbeta3, alpha5beta1) in CRC cells (HT29, CX1.1) is induced by Tbeta4 and VEGF-A only when they grow in 3D fibrin gels but not in 2D ones. The cells growing in 3D fibrin gels release upon Tbeta4 significant amounts of active MMPs (MMP-2, MMP-9, and MMP-7) that cause extensive proteolysis in their close vicinity. As evidenced by a variety of approaches (transfection experiments, coimmunoprecipitation, gene silencing with siRNA), we found that this involves interaction of Tbeta4 with Ku80, which has recently been described by us to mediate Tbeta4 intracellular activity.

Topics: Cell Movement; Cells; Colonic Neoplasms; Endothelial Cells; Extracellular Matrix; Humans; Integrins; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Neoplasms; RNA, Small Interfering; Signal Transduction; Thymosin; Vascular Endothelial Growth Factor A

The hepatitis C virus (HCV) is a global public health problem, with chronic infection leading to development of cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). Treatment of HCV is suboptimal with overall response rates of slightly greater than 50% when patients are treated with pegylated interferon alfa and ribavirin. Thymosin alpha 1 (Talpha1; TA-1) is an immunomodulatory peptide with intrinsic activities that might improve treatment outcomes for HCV by incorporation of this agent in current treatment paradigms. An extensive body of literature supports a possible role for this agent in difficult to treat populations. However, clinical trials to date have failed to conclusively support the role of TA-1 in combination interferon-based therapies. Therefore, the promise of TA-1 adjunctive therapy for HCV remains, but the proof will require investment in large randomized clinical trials of appropriate patient populations.

Topics: Carcinoma, Hepatocellular; Chronic Disease; Clinical Trials as Topic; Hepacivirus; Humans; Interferons; Liver Cirrhosis; Liver Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Ribavirin; Thymalfasin; Thymosin; Treatment Outcome

Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein with pleiotropic immune enhancing activity. IRX-2 is a primary cell-derived biologic containing multiple cytokines that enhance dendritic cell maturation, promote T-cell growth and differentiation, and inhibit tumor-mediated apoptosis of T cells. IRX-2 is being developed as an immunotherapeutic agent as a novel T-cell adjuvant platform for vaccines as well. Based on their biological activities, thymosin alpha1 and IRX-2 were predicted to exhibit synergistic effects when evaluated in animal and human studies. In animal studies, the combination of IRX-2 and Talpha1 (IRX-3) increased T-cell numbers compared to either alone during recovery from hydrocortisone mediated reduction. IRX-3 further enhanced reduction in tumor burden following chemotherapy compared to IRX-2. Based on these studies, IRX-3 is predicted to be especially important in a setting where reversal of immune suppression due to the presence of tumor, irradiation, and/or chemotherapy is likely to be an important factor in cytokine activity.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Cell Differentiation; Cytokines; Dendritic Cells; Humans; Mice; Neoplasms; T-Lymphocytes; Thymalfasin; Thymosin

Thymosin beta 10 (Tbeta10) is a member of the beta-thymosin family, which has biological activities as an actin-sequestering protein involved in cell motility. Tbeta10 may be correlated with tumor biology such as cell proliferation, apoptosis, angiogenesis, and metastasis behavior. However, the molecular mechanisms of action of Tbeta10 in cancer are largely unknown. Tbeta10 is differentially expressed in embryogenesis and neuronal development. Its expression is also increased in many inflammatory conditions and tumorigenesis. This review briefly summarizes recent advances in Tbeta10 research including differential expression, functions, mechanisms, gene regulation, and therapeutic applications in cancer, wound healing, and other diseases.

Topics: Actins; Animals; Apoptosis; Cell Movement; Cell Proliferation; Gene Expression Regulation; Humans; Inflammation; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Neurogenesis; Neurons; Signal Transduction; Thymosin; Wound Healing

Prothymosin alpha (ProTalpha) is a small molecule of natively unstructured acidic protein, and widely exists in mammalian tissues. Nevertheless, its biological functions are still elusive. Recent studies indicate that ProTalpha is involved in carcinogenesis and cancer development. We reviewed current reports on the potential roles of ProTalpha in cell proliferation, carcinogenesis, apoptosis, and immunomodulatory, discussed the regulation of ProTalpha gene expression and possible molecular mechanisms underlying its internal and external actions in cells, and explored its significance in tumor diagnosis and treatment.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Genetic Therapy; Humans; Neoplasms; Protein Precursors; Thymosin

Thymosin alpha1 (Talpha1), first described and characterized by Allan Goldstein in 1972, is used worldwide for the treatment of some immunodeficiencies, malignancies, and infections. Although Talpha1 has shown a variety of effects on cells and pathways of the immune system, its central role in modulating dendritic cell (DC) function has only recently been appreciated. As DCs have the ability to sense infection and tissue stress and to translate collectively this information into an appropriate immune response, an action on DCs would predict a central role for Talpha1 in inducing different forms of immunity and tolerance. Recent results have shown that Talpha1: (a) primed DCs for antifungal Th1 resistance through Toll-like receptor (TLR)/MyD88-dependent signaling and this translated in vivo in protection against aspergillosis; (b) activated plasmacytoid DCs (pDC) via the TLR9/MyD88-dependent viral recognition, thus leading to the activation of interferon regulatory factor 7 and the promotion of the IFN-alpha/IFN-gamma-dependent effector pathway, which resulted in vivo in protection against primary murine cytomegalovirus infection; (c) induced indoleamine 2,3-dioxygenase activity in DCs, thus affecting tolerization toward self as well as microbial non-self-antigens, and this resulted in vivo in transplantation tolerance and protection from inflammatory allergy. Talpha1 is produced in vivo by cleavage of prothymosin alpha in diverse mammalian tissues. Our data qualify Talpha1 as an endogenous regulator of immune homeostasis and suggest that instructive immunotherapy with Talpha1, via DCs and tryptophan catabolism, could be at work to control inflammation, immunity, and tolerance in a variety of clinical settings.

Topics: Acquired Immunodeficiency Syndrome; Animals; Aspergillosis; Dendritic Cells; HIV Infections; Homeostasis; Humans; Hypersensitivity; Immunity, Innate; Inflammation; Mycoses; Neoplasms; Signal Transduction; Th1 Cells; Thymalfasin; Thymosin; Thymus Gland

The early stages of angiogenesis are usually accompanied by the occurrence of vascular leakage, and the deposition of fibrin in extravascular spaces. Initially, the fibrin network acts as a sealing matrix, but later on also as a scaffolding for invading endothelial cells. This process is induced by angiogenic growth factors, particularly by vascular endothelial growth factor (VEGF). Angiogenesis involves proteolytic activities, in particular cell-bound urokinase/plasmin and matrix metalloproteinase (MMPs) activities that modulate the fibrin structure and affect adhesion and migration of endothelial cells. Recent data show that formation of new vessels may be stimulated by thymosin beta-4 (Tbeta-4), but it is still not clear whether Tbeta-4 alone is angiogenic or the angiogenic potential of Tbeta-4 is mediated by VEGF. In this report to further characterize Tbeta-4 angiogenic activity, we produced its mutants that were deprived of the N-terminal tetrapeptide AcSDKP (Tbeta-4((AcSDKPT/4A))), the actin-binding sequence KLKKTET (Tbeta-4((KLKKTET/7A))) and with the nuclear localization sequence damaged by a point mutation Lys16Ala (Tbeta-4((K16A))). Then we tested their activity to induce expression and release of MMPs as well as plasminogen activators inhibitor type-1 (PAI-1). We also analyzed their effect on migration and proliferation of endothelial cells in three-dimensional (3D) fibrin matrix as well as on their ability to stimulate the outgrowth of human endothelial cells in capillary-like tubular structures. Our data demonstrate that increased intracellular expression of Tbeta-4 and its mutants is necessary and sufficient to induce PAI-1 gene expression in endothelial cells. Similarly, they stimulate expression and release of MMP-1, -2, and -3. As evaluated by using specific inhibitors to these MMPs, they modified specifically the structure of fibrin and thus facilitated migration of endothelial cells. To sum up, our data show that the mechanism by which Tbeta-4 induced transition of endothelial cells from quiescent to proangiogenic phenotype is characterized by increased expression of PAI-1 and MMPs did not require the presence of the N-terminal sequence AcSDKP, and depended only partially on its ability to bind G-actin or to enter the nucleus.

Topics: Amino Acid Sequence; Animals; Cell Adhesion; Cell Movement; Endothelial Cells; Humans; Mice; Molecular Sequence Data; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Thymosin

Here we review the mechanisms by which Thymosin beta4 (Tbeta4) regulates angiogenesis, its role in processes, such as wound healing and tumour progression and we discuss in more detail the role of Tbeta4 in the cardiovascular system and significant recent findings implicating Tbeta4 as a potential therapeutic agent for ischaemic heart disease.

Topics: Animals; Humans; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Thymosin; Wound Healing

Thymosins are small peptides, originally identified from the thymus, but now known to be more widely distributed in many tissues and cells. Thymosins are divided into three main groups, alpha-, beta-, : and gamma-thymosins, based on their isoelectric points. alpha-thymosins (ProTalpha, Talphal) have nuclear localization and are involved in transcription and/or DNA replications; whereas beta-thymosins (Tbeta4, Tbeta10, Tbetal5) have cytoplasmic localization and show high affinity to G-actin for cell mobility. Furthermore, it is well known that both alpha- and beta-thymosins play important roles in modulating immune response, vascular biology, and cancer pathogenesis. More importantly, thymosins may have significant clinical applications. They may serve as molecular markers for the diagnosis and prognosis of certain diseases. In addition, they could be molecular targets of certain diseases or be used as therapeutic agents to treat certain diseases. However, the molecular mechanisms of action of thymosins are largely unknown. This review not only presents recent advances of basic science research of thymosins and their clinical applications but provides thoughtful views for future directions of investigation on thymosins.

Topics: Animals; Endothelial Cells; Humans; Neoplasms; Prognosis; Thymosin

Here, we review the biochemical and molecular properties of thymosin beta(4) (Tbeta(4)), the major actin-sequestering molecule in eukaryotic cells, and its key role in dermal- and corneal-wound healing. Tbeta(4) has several, novel, potential clinical applications in the repair and remodeling of ulcerated tissues and solid organs following hypoxic injuries, such as myocardial infarction and stroke. It might also have important repair functions in the pathophysiologic sequelae that are associated with actin toxicity and with septic shock, such as respiratory distress syndrome, multi-organ failure and severe tissue trauma.

Topics: Actins; Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Neoplasms; Thymosin; Wound Healing

This paper will review the historical background that has generated our present interest in the actions of the thymosins in biological therapy. It will also discuss the multiple actions of the thymosins in the immune, endocrine and central nervous systems. The isolation from the thymus gland of the thymosins, a family of biologically active molecules with hormone-like properties, was first described in 1966 by AL Goldstein and A White. Since that time, significant progress has been made in understanding the role of the thymosins in immunity and the nature of the growth factors, cytokines and chemokines they modulate. The thymosins include a family of biochemically and functionally distinct polypeptides with clinically important physiological properties. In the early 1970s, preclinical studies establishing the immunorestorative effects of a partially purified thymosin preparation termed thymosin fraction 5 (TF5) provided the scientific foundation for the first clinical trials with TF5 in 1974. TF5 was effective in turning on the immune systems of a number of children with DiGeorge syndrome and other thymic dysplasias. These trials led to further interest in the active components in TF5 and to the chemical characterisation of the biologically active thymosins. Several of these molecules are showing significant promise in the clinic in the areas of cancer, infectious diseases and wound healing.

Topics: Amino Acid Sequence; Autoimmune Diseases; Humans; Immunotherapy; Molecular Sequence Data; Neoplasms; Stress, Physiological; Thymosin

The studies on thymosins were initiated in 1965, when the group of A. White searched for thymic factors responsible for the physiological functions of thymus. To restore thymic functions in thymic-deprived or immunodeprived animals, as well as in humans with primary immuno-deficiency diseases and in immunosuppressed patients, a standardized extract from bovine thymus gland called thymosin fraction 5 was prepared. Thymosin fraction 5 indeed improved immune response. It turned out that thymosin fraction 5 consists of a mixture of small polypeptides. Later on, several of these peptides (polypeptide beta 1, thymosin alpha 1, prothymosin alpha, parathymosin, and thymosin beta 4) were isolated and tested for their biological activity. The research of many groups has indicated that none of the isolated peptides is really a thymic hormone; nevertheless, they are biologically important peptides with diverse intracellular and extracellular functions. Studies on these functions are still in progress. The current status of knowledge of structure and functions of the thymosins is discussed in this review.

Topics: Actins; Amino Acid Sequence; Animals; Caspase 3; Caspases; Cell Division; Humans; Molecular Sequence Data; Neoplasms; Neovascularization, Physiologic; Phosphorylation; Phylogeny; Protein Precursors; Thymosin; Wound Healing; Zinc

Multiple therapeutic approaches have been tested in different experimental tumour models and in human cancers. Most part of them are based on the hypothesis that the inhibition of tumour growth requires a strong immune response in which a main role is played by CTLs. It is known, however, that an efficient CTL response requires expression of tumour antigens, MHC class I surface molecules presentation, expression of different co-stimulatory molecules and a sustained generation and proliferation of specific cytotoxic CD8+ cells with an efficient CD4+ cooperation. In this context, our group has extensively explored a protocol of combined therapy consisting of the use of chemotherapeutic agents associated with thymosin alpha 1 (Talpha 1) and different cytokines, whose efficacy has been demonstrated in experimental models as well as in human cancers. In this manuscript, the main data supporting a pivotal role of Talpha 1 in such combination protocols are reviewed. In particular, a special mention of the molecular mechanisms underlying the effects of Talpha 1 on immune effector cells as well as on target tumour cells is provided. These data contribute to explain the mechanism of action of Talpha 1, when used in combination therapy, for the treatment of cancer and provide new insights in predicting further possible applications of this peptide in other pathological conditions.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Combined Chemotherapy Protocols; Cytokines; Disease-Free Survival; Humans; Neoplasms; Thymalfasin; Thymosin

Thymosin alpha1 (Talpha1), a synthetic 28-amino acid peptide with multiple biological activities primarily directed towards immune response enhancement, was originally developed by Alpha 1 Biomedicals for the treatment of hepatitis B virus (HBV) infection. SciClone developed and launched Talpha1, under the trade name Zadaxin, for the treatment of HBV and hepatitis C virus (HCV) infections. The drug is also being developed for the treatment of non-small cell lung cancer (NSCLC), hepatocellular carcinoma, AIDS and malignant melanoma. Talpha1 is able to potentiate the action of cytokines and also reduce the hematological toxicity of cytotoxic drug therapy (cyclophosphamide-, 5-fluorouracil-, dacarbazine- or ifosfamide-based regimens). These studies also demonstrated the mechanism of action of Talpha1 and its role as an immune system enhancer. By July 2001, it was in phase III trials in the US in combination with PEGylated interferon-alpha, and later the same month it was approved in the Philippines. SciClone received expanded approval for HBV and HCV infection in Mexico in July 2001. Talpha1 has been launched in Argentina, China, Peru, the Philippines and Singapore for the treatment of chronic HBV infection. The product subsequently received expanded approval for the treatment of both HBV and HCV infection in Argentina. Marketing approval was granted in India for HBV infection in February 2001. The company was working to expand this approval to include HCV infection. In March 2000, approval for treatment of HBV infection was granted in Thailand, Laos and Malta. Approval was also granted in Sri Lanka and Brunei in August 1999. In September 2000, SciClone announced that approval had been expanded to include the treatment of HCV infection as well as the previously approved HBV indication in both Peru and Sri Lanka. In January 1999, SciClone received approval for Talpha1 in Venezuela for the treatment of HBV and HCV infection. The company also filed a marketing application in New Zealand for Talpha1 to treat HBV infection. The drug was approved in South Korea in April 2000, as an influenza vaccine adjuvant and this was expected to be expanded to indude use for treatment of both HBV and HCV infections. In July 2001, it was approved in In September and October 2000, SciClone was granted patents in Mexico and Canada, respectively, for the use of Talpha1 for the treatment of HCV infection. In June 2000, SciClone was issued a Notice of Allowance by the US Patent and

Topics: Adjuvants, Immunologic; Animals; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Injections, Subcutaneous; Neoplasms; Structure-Activity Relationship; Thymalfasin; Thymosin; Virus Diseases

The beta-thymosins are a family of highly conserved polar 5 kDa peptides originally thought to be thymic hormones. About 10 years ago, thymosin beta(4) as well as other members of this ubiquitous peptide family were identified as the main intracellular G-actin sequestering peptides, being present in high concentrations in almost every cell. beta-Thymosins bind monomeric actin in a 1:1 complex and act as actin buffers, preventing polymerization into actin filaments but supplying a pool of actin monomers when the cell needs filaments. Changes in the expression of beta-thymosins appear to be related to the differentiation of cells. Increased expression of beta-thymosins or even the synthesis of a beta-thymosin normally not expressed might promote metastasis possibly by increasing mobility of the cells. Thymosin beta(4) is detected outside of cells in blood plasma or in wound fluid. Several biological effects are attributed to thymosin beta(4), oxidized thymosin beta(4), or to the fragment, acSDKP, possibly generated from thymosin beta(4). Among the effects are induction of metallo-proteinases, chemotaxis, angiogenesis and inhibition of inflammation as well as the inhibition of bone marrow stem cell proliferation. However, nothing is known about the molecular mechanisms mediating the effects attributed to extracellular beta-thymosins.

Topics: Actins; Amino Acid Sequence; Animals; Binding Sites; Cell Differentiation; Cell Movement; Humans; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oxidation-Reduction; RNA, Messenger; Thymosin; Wound Healing

The thymus is an endocrine organ. A unified, physiological concept of humoral regulations of the immune response has emerged in the last three decades. The thymus is the major site of production of immunocompetent T lymphocytes from their hematopoietic stem cells. This complex process required direct cell to cell, receptor based interactions, as well as in situ paracrine information via the numerous cytokines and thymic hormones produced by the cells of thymic microenvironment. Thymic hormones induce in situ T-cell marker differentiation, expression and functions. These polypeptide hormones have also been shown by means of immunocytochemistry to localize in the reticulo-epithelial (RE) cells of the thymic cellular microenvironment. Due to the great complexity of the intrathymic maturation sequence of T lymphocytes and the diverse immunophenotypically unique subpopulations of T lymphocytes, it is quite unlikely that a single thymic humoral factor could control all of the molecular steps and cell populations involved. It is much more likely that an extremely rich and diverse, but genetically determined, milieu is present within the thymus, and that thus the control of intrathymic T lymphocyte maturation and the functional maturation of T cells involves the orchestral interaction of various thymic-specific factors and other molecules during the differentiation process. Thymosin fraction 5 and its constituent peptides influence several properties of lymphocytes including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production, as well as the expression of various cell surface maturation/differentiation markers. Recently, derivatives of thymic hormones, mostly of thymosins, have been detected as products of neoplastically transformed cells and employed in the early diagnosis of neoplasms. In clinical trials, thymic hormones strengthen the effects of immunomodulators in immunodeficiencies, autoimmune diseases, and neoplastic malignancies. Combined chemo-immunotherapeutical anti-cancer treatment seems to be more efficacious than chemotherapy alone, and the significant hematopoietic toxicity associated with most chemotherapeutical clinical trials can be reduced significantly by the addition of immunotherapy.

Topics: Biomarkers, Tumor; Humans; Neoplasms; Oligopeptides; Protein Precursors; Thymalfasin; Thymopentin; Thymosin; Thymus Hormones

Many studies have explored the effects of immunotherapy, alone or in combination with conventional therapies, on both experimental and human cancers. Evidence has been provided that combined treatments with thymosin alpha 1 (T alpha 1) and low doses of interferon (IFN) or interleukin (IL)-2 are highly effective in restoring several immune responses depressed by tumor growth and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to increase the anti-tumor effect of chemotherapy while markedly reducing the general toxicity of the treatment. The advantages of using this combined chemo-immunotherapeutic approach in experimental and human cancers are reviewed in this issue.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Combined Modality Therapy; Humans; Immunotherapy; Neoplasms; Thymalfasin; Thymosin

T alpha 1, a 28-amino-acid peptide, is derived from PT alpha, which is an intracellular, nonsecretory protein of unknown function. Both T alpha 1 and PT alpha are found in the blood of normal individuals. Subcutaneous and intramuscular injections of T alpha 1 in doses up to 9.6 mg/m2 are tolerated without side effects, and 0.9 mg/m2 injections raise the serum level approximately 30-fold after 1 hr of administration, which slowly returns to baseline within 24 hr. In vitro, and perhaps in vivo, T alpha 1 restores normal T-cell function. It increases IL-2 production and IL-2 receptors in normal mitogen-stimulated T cells and stimulates IL-3 production in immunocompromised mice. The dose-response relationship for these effects is not linear and may be bimodal. T alpha 1 binds to VIP receptors and inhibits in vitro and xenograft growth of non-SCLC cell lines. In patients with nonbulky carcinomas who have received standard therapy, T alpha 1 is possibly effective in prolonging the time to relapse and in improving survival. At present there is a great need to clearly define the clinical role of T alpha 1 in cancer patients. A major problem encountered in studies with T alpha 1 will, however, be the present lack of knowledge with regard to its mechanism in effecting tumor growth. It is not at all clear whether its immunomodulatory functions, its interaction with VIP receptors, or none of these mechanisms are related to its antineoplastic activities. In addition, the apparent nonlinear dose-response relationship will make it difficult to choose a reasonable dosing schedule for clinical trials. This is particularly apparent in light of the experimental animal data summarized above where a tumor response was seen at doses of 4 micrograms/kg and 400 micrograms/kg but not at 0.4 microgram/kg and 40 micrograms/kg. This dose range could conceivably be given to humans since 9.6 mg/m2, the maximum dose given to humans without major side effects to date, is roughly equivalent to 250 micrograms/kg. At this time a reasonable clinical approach would be a well-designed risk factor stratified phase III clinical trial using 0.9 mg/m2 T alpha 1 subcutaneously twice a week compared to a control group to substantiate the data reported by Schulof et al. Before such data are available, T alpha 1 should not be used in clinical oncology.

Topics: Adjuvants, Immunologic; Animals; Clinical Trials as Topic; Humans; Mice; Neoplasms; Thymalfasin; Thymosin

Topics: Acquired Immunodeficiency Syndrome; Humans; Neoplasms; Thymalfasin; Thymosin

For years, scientists have searched for ways to trigger the body's own defenses against cancer and other diseases associated with abnormal immunity. This search has led to the discovery of a number of important new biological and chemical substances that augment, direct or restore many of the normal defenses of the body. These substances are in essence the natural drugs of the body that endow us with immunity and resistance to disease. Now called biological response modifiers (BRMs), most of these 'new medicines', such as thymosins, lymphokines, and interferons, occur naturally in the body, while others, synthetic immunomodulators and thymomimetic agents (drugs that mimic thymic function) have been created in the laboratory. Previously, therapeutic drug development in this area relied upon chemical synthesis or introduction of bacterial adjuvants, or modified viral compounds and substances, which were foreign to the body. Therefore, they did not and do not rely upon or use the body's natural immune and biological response systems for protection against disease, function and response to the environment. Although scientists have known about BRMs for years, isolating and purifying them so that they could be used to treat diseases has been extremely difficult. Many of these substances, such as the lymphokines, occur in the body in minute amounts and normally do not circulate in the blood. The development of new technologies for isolation and large scale synthesis, e.g. solid phase peptide synthesis, high-pressure liquid chromatography microsequencing and genetic engineering, has now permitted scientists to isolate, purify, and synthesize BRMs in sufficiently large quantities to allow human clinical trials. In this paper we will focus on the potential clinical applications of the thymosins and anti-thymosins.

Topics: Acquired Immunodeficiency Syndrome; Aging; Amino Acid Sequence; Humans; Immune Tolerance; Immunotherapy; Models, Biological; Molecular Weight; Neoplasms; Stress, Physiological; Thymosin

The manuscript will provide an in-depth and critical review of the nomenclature, biochemistry, biological properties, and a summary of published and on-going clinical trials with all reported thymic preparations, including both partially purified thymic factors (e.g., thymosin fraction 5, thymostimulin) as well as purified and synthesized thymic peptides (e.g., thymosin alpha 1, thymulin). Particular emphasis will be placed on which thymic peptides should be categorized as true hormones. In addition, the comparative biochemistry and biological activity in animals will be summarized and contrasted for all the currently available thymic factors. The effects, in vitro of thymic factors, on peripheral blood lymphocytes isolated from normal donors and patients with primary immunodeficiency disorders, autoimmune disorders, and neoplastic disorders will also be reviewed. Finally, a detailed critical summary of the clinical trials performed with each of the thymic preparations will be presented with an emphasis on treatment of patients with cancer.

Topics: Amino Acid Sequence; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Autoimmune Diseases; Biological Assay; Cell Differentiation; Epithelium; Humans; Immunologic Deficiency Syndromes; Immunotherapy; Neoplasms; T-Lymphocytes; Terminology as Topic; Thymectomy; Thymic Factor, Circulating; Thymopoietins; Thymosin; Thymus Extracts; Thymus Gland; Thymus Hormones

Topics: Antineoplastic Agents; Cell Differentiation; Drug Therapy, Combination; Humans; Interferons; Lymphocytes; Neoplasms; T-Lymphocytes; Terminology as Topic; Thymosin; Thymus Hormones

Biological response modifiers are agents capable of affecting the host immune response toward tumors and include those biological substances produced by the human mammalian cell genome. Interferons and other lymphokines, tumor antigens, antibodies and agents which can activate or stimulate host immune responses are all included in this general category of agents. With the advent of genetic engineering and with monoclonal antibody technology, highly pure preparations of these biological substances can now be produced for tests of activity in preclinical models and in man. As the initial results accrue with highly purified preparations of interferon and with monoclonal antibodies alone or conjugated to toxic substances, the possibility of tumor specific therapy is becoming a reality. The development of preclinical models to predict for clinical activity remains a most important task to attempt to bring to clinical trials the substances most likely to be efficacious as anticancer agents. Early clinical results indicate that many of these agents can give responses in patients with clinically perceptible disease and Phase II activity studies are just beginning to define the range of clinical activity for a variety of biological response modifying agents. The development of biological response modifiers through preclinical testing and into clinical trials will be discussed in detail.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; BCG Vaccine; Cell Wall Skeleton; Child; Clinical Trials as Topic; Drug Evaluation; Humans; Immunotherapy; Interferons; Interleukin-1; Interleukin-2; Levamisole; Lymphokines; Macrophage-Activating Factors; Mucoproteins; Mycolic Acids; Neoplasms; Pyran Copolymer; Thymosin; Vaccination

Topics: Animals; Autoimmune Diseases; Growth Inhibitors; Humans; Immunity; Immunologic Deficiency Syndromes; Interferons; Interleukin-1; Interleukin-2; Lymphotoxin-alpha; Neoplasms; Thymic Factor, Circulating; Thymosin; Thymus Hormones; Transfer Factor

Topics: Aging; Amino Acid Sequence; Animals; Animals, Newborn; Blood Proteins; Cattle; Clinical Trials as Topic; Humans; Isoelectric Focusing; Mice; Neoplasms; Peptides; Rats; Thymectomy; Thymic Factor, Circulating; Thymopoietins; Thymosin; Thymus Gland; Thymus Hormones

Topics: Adolescent; Aging; Amino Acid Sequence; Animals; Bone Marrow; Brain; Child; Child, Preschool; Drug Evaluation; Epithelium; Female; Humans; Infant; Male; Mice; Neoplasms; Radioimmunoassay; Spleen; Thymosin; Thymus Gland; Thymus Hormones

Topics: Adjuvants, Immunologic; Animals; Aziridines; BCG Vaccine; Breast Neoplasms; Cyclophosphamide; Dose-Response Relationship, Immunologic; Humans; Immunotherapy; Leucine; Leukemia L1210; Leukemia, Lymphoid; Levamisole; Lymphoma, Non-Hodgkin; Melanoma; Methotrexate; Mice; Neoplasms; Propionibacterium acnes; T-Lymphocytes, Regulatory; Thymosin

Important contributions that stimulated studies in cancer immunotherapy included: (1) the discovery of tumour-associated antigens; (2) the observation that infection with bacille Calmette-Guérin (BCG) in animals was protective against tumour challenge; and (3) the observation that immunodepression due either to malignant disease or to treatment of the disease, was, in some instances, related to prognosis. Immunotherapy trials with microbial agents have involved attempts to obtain a local effect by injecting the agent into the tumour or into the region of the tumour and to obtain a "systemic" effect distant from the site of injection. Trials with active specific immunotherapy involving tumour cells or tumour cell extracts have frequently involved the combination of these specific agents with a nonspecific adjuvant such as BCG. Recent studies with thymosin and levamisole in patients with lung cancer and other types of malignant disease have shown prolonged survival in the groups receiving immunotherapy.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; BCG Vaccine; Humans; Hypersensitivity, Delayed; Immunotherapy; Leukemia, Lymphoid; Levamisole; Melanoma; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Skin Neoplasms; Thymosin

Thymosin fraction 5 contains several distinct hormonal-like factors which are effective in partially or fully inducing and maintaining immune function. Several of the peptide components of fraction 5 have been purified, sequenced and studied in assay systems designed to measure T-cell differentiation and function. These studied indicate that a number of the purified peptides act on different subpopulations of T-cells (see Figure 1). Thymosin beta 3 and beta 4 peptides act on terminal deoxynucleotidyl transferase (TdT) negative precursor T-cells to induce TdT positive cells. Thymosin alpha 1 induces the formation of functional helper cells and conversion of Lyt- cells to Lyt 1+, 2+, 3+ cells. Thymosin alpha 7 induces the formation of functional suppressor T-cells and also converts Lyt- cells to Lyt 1+, 2+, 3+ cells. These studies have provided further evidence that the thymus secretes a family of distinct peptides which act at various sites of the maturation sequence of T-cells to induce and maintain immune function. Phase I and Phase II clinical studied with thymosin in the treatment of primary immunodeficiency diseases, autoimmune diseases, and cancer point to a major role of the endocrine thymus in the maintenance of immune balance and in the treatment of diseases characterized by thymic malfunction. It is becoming increasingly clear that immunological maturation is a process involving a complex number of steps and that a single factor initiating a single cellular event might not be reflected in any meaningful immune reconstitution unless it is the only peptide lacking. Given the complexity of the maturation sequence of T-cells and the increasing numbers of T-cell subpopulations that are being identified, it would be surprising if a single thymic factor could control all of the steps and populations involved. Rather, it would appear that the control of T-cell maturation and function involves a complex number of thymic-specific factors and other molecules that rigidly control the intermediary steps in the differentiation process.

Topics: Amino Acid Sequence; Animals; Autoimmune Diseases; Chemical Phenomena; Chemistry; Humans; Immunologic Deficiency Syndromes; Immunotherapy; Neoplasms; Peptide Fragments; T-Lymphocytes; Thymosin; Thymus Gland; Thymus Hormones

Topics: Amino Acid Sequence; Animals; Humans; Immunity; Immunologic Deficiency Syndromes; Isoelectric Focusing; Mice; Neoplasms; T-Lymphocytes; Terminology as Topic; Thymectomy; Thymosin; Thymus Gland; Thymus Hormones

Topics: Animals; Cattle; Humans; Immunologic Deficiency Syndromes; Mice; Mononuclear Phagocyte System; Neoplasms; Peptides; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: BCG Vaccine; Bone Marrow Transplantation; Humans; Immunologic Deficiency Syndromes; Immunotherapy; Mycobacterium bovis; Neoplasms; Thymosin; Thymus Gland; Transfer Factor; Transplantation, Homologous

Topics: Age Factors; Animals; Antibody-Dependent Cell Cytotoxicity; Cytotoxicity, Immunologic; Environment; Female; Genotype; Guinea Pigs; Humans; Immunity, Cellular; Immunity, Innate; Immunosuppression Therapy; In Vitro Techniques; Killer Cells, Natural; Male; Mice; Neoplasms; Neoplasms, Experimental; Organ Specificity; Rats; Species Specificity; T-Lymphocytes; Thymosin; Thymus Gland

Topics: Adjuvants, Immunologic; Antigens, Neoplasm; Antineoplastic Agents; BCG Vaccine; Epitopes; Humans; Immunity, Cellular; Immunosuppression Therapy; Immunotherapy; Levamisole; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Propionibacterium acnes; RNA; Thymosin; Transfer Factor

Topics: Aging; Animals; Autoimmune Diseases; Disease Models, Animal; Humans; Immunity; Immunologic Deficiency Syndromes; Immunologic Techniques; Leukemia; Neoplasms; T-Lymphocytes; Thymosin; Thymus Gland; Thymus Hormones

Topics: Animals; Antibody Formation; BCG Vaccine; Humans; Immune Adherence Reaction; Immunity, Active; Immunity, Maternally-Acquired; Immunotherapy; Neoplasms; Neuraminidase; Thymosin; Transfer Factor

Biological response modifiers are agents capable of affecting the host immune response toward tumors and include those biological substances produced by the human mammalian cell genome. Interferons and other lymphokines, tumor antigens, antibodies and agents which can activate or stimulate host immune responses are all included in this general category of agents. With the advent of genetic engineering and with monoclonal antibody technology, highly pure preparations of these biological substances can now be produced for tests of activity in preclinical models and in man. As the initial results accrue with highly purified preparations of interferon and with monoclonal antibodies alone or conjugated to toxic substances, the possibility of tumor specific therapy is becoming a reality. The development of preclinical models to predict for clinical activity remains a most important task to attempt to bring to clinical trials the substances most likely to be efficacious as anticancer agents. Early clinical results indicate that many of these agents can give responses in patients with clinically perceptible disease and Phase II activity studies are just beginning to define the range of clinical activity for a variety of biological response modifying agents. The development of biological response modifiers through preclinical testing and into clinical trials will be discussed in detail.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; BCG Vaccine; Cell Wall Skeleton; Child; Clinical Trials as Topic; Drug Evaluation; Humans; Immunotherapy; Interferons; Interleukin-1; Interleukin-2; Levamisole; Lymphokines; Macrophage-Activating Factors; Mucoproteins; Mycolic Acids; Neoplasms; Pyran Copolymer; Thymosin; Vaccination

Topics: Antigens, Surface; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Humans; Kinetics; Leukocyte Count; Lung Neoplasms; Lymphocyte Culture Test, Mixed; Neoplasms; Rosette Formation; T-Lymphocytes; Thymalfasin; Thymosin

Topics: Adolescent; Adult; Aged; Animals; Arthritis, Rheumatoid; Child; Clinical Trials as Topic; Double-Blind Method; Humans; Immunologic Deficiency Syndromes; Middle Aged; Neoplasms; Rats; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Aging; Amino Acid Sequence; Animals; Animals, Newborn; Blood Proteins; Cattle; Clinical Trials as Topic; Humans; Isoelectric Focusing; Mice; Neoplasms; Peptides; Rats; Thymectomy; Thymic Factor, Circulating; Thymopoietins; Thymosin; Thymus Gland; Thymus Hormones

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Division; Clinical Trials as Topic; Cytological Techniques; Drug Evaluation, Preclinical; Fluorometry; Humans; Ifosfamide; Immunotherapy; In Vitro Techniques; Lung Neoplasms; Neoplasms; Thymosin

Topics: Clinical Trials as Topic; Complement C3; Complement C4; Hodgkin Disease; Humans; Leukocyte Count; Neoplasms; Pokeweed Mitogens; Rosette Formation; Skin Tests; Streptodornase and Streptokinase; T-Lymphocytes; Thymosin; Thymus Hormones

Thymosin α-1 (Tα-1) is an immunomodulating polypeptide of 28 amino acids, which was the first peptide isolated from thymic tissue and has been widely used for the treatment of viral infections, immunodeficiencies, and especially malignancies. Tα-1 stimulates both innate and adaptive immune responses, and its regulation of innate immune cells and adaptive immune cells varies under different disease conditions. Pleiotropic regulation of immune cells by Tα-1 depends on activation of Toll-like receptors and its downstream signaling pathways in various immune microenvironments. For treatment of malignancies, the combination of Tα-1 and chemotherapy has a strong synergistic effect by enhancing the anti-tumor immune response. On the basis of the pleiotropic effect of Tα-1 on immune cells and the promising results of preclinical studies, Tα-1 may be a favorable immunomodulator to enhance the curative effect and decrease immune-related adverse events of immune checkpoint inhibitors to develop novel cancer therapies.

Topics: Adjuvants, Immunologic; Humans; Immunity; Neoplasms; Thymalfasin; Thymosin; Tumor Microenvironment

The study of mechanism of action of Thymosin alpha 1 (Tα1) and the basis of the pleiotropic effect in health and disease, is one of the main focus of our ongoing research. Tα1 is a thymic peptide that demonstrates a peculiar ability to restore homeostasis in different physiological and pathological conditions (i.e., infections, cancer, immunodeficiency, vaccination, and aging) acting as multitasking protein depending on the host state of inflammation or immune dysfunction. However, few are the information about mechanisms of action mediated by specific Tα1-target protein interaction that could explain its pleiotropic effect. We investigated the interaction of Tα1 with Galectin-1 (Gal-1), a protein belonging to an oligosaccharide binding protein family involved in a variety of biological and pathological processes, including immunoregulation, infections, cancer progression and aggressiveness. Using molecular and cellular methodological approaches, we demonstrated the interaction between these two proteins. Tα1 specifically inhibited the hemagglutination activity of Gal-1, the Gal-1 dependent in vitro formation of endothelial cell tubular structures, and the migration of cancer cells in wound healing assay. Physico-chemical methods revealed the details of the molecular interaction of Tα1 with Gal-1. Hence, the study allowed the identification of the not known until now specific interaction between Tα1 and Gal-1, and unraveled a novel mechanism of action of Tα1 that could support understanding of its pleiotropic activity.

Topics: Galectin 1; Humans; Neoplasms; Thymalfasin; Thymosin

Members of the α-thymosin family have long been studied for their immunostimulating properties. Among them, the danger-associated molecular patterns (DAMPs) prothymosin α (proTα) and its C-terminal decapeptide proTα(100-109) have been shown to act as immunomodulators in vitro, due to their ability to promote T helper type 1 (Th1) responses. Recently, we verified these findings in vivo, showing that both proTα and proTα(100-109) enhance antitumor-reactive T cell-mediated responses.. In view of the eventual use of proTα and proTα(100-109) in humans, we investigated their safety profile in silico, in human leukocytes and cancer cell lines in vitro, and in immunocompetent mice in vivo, in comparison to the proTα derivative thymosin alpha 1 (Τα1), a 28-mer peptide extensively studied for its safety in clinical trials.. In silico prediction via computational tools showed that all three peptide sequences likely are non-toxic or do not induce allergic regions. In vitro, pro- Tα, proTα(100-109) and Tα1 did not affect the viability of human cancer cell lines and healthy donor-derived leukocytes, did not promote apoptosis or alter cell cycle distribution. Furthermore, mice injected with proTα, proTα(100-109) and Tα1 at doses equivalent to the suggested dose regimen of Tα1 in humans, did not show signs of acute toxicity, whereas proTα and proTα(100-109) increased the levels of proinflammatory and Th1- type cytokines in their peripheral blood.. Our preliminary findings suggest that proTα and proTα(100-109), even at high concentrations, are non-toxic in vitro and in an acute toxicity model in vivo; moreover, we show that the two peptides retain their immunomodulatory properties in vivo and, eventually, could be considered for therapeutic use in humans.

Topics: Animals; Cytokines; Humans; Immunologic Factors; Mice; Neoplasms; Peptides; Thymosin

Topics: Animals; B-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Female; Immunologic Factors; Interleukin-2; Macrophages; Mice; Neoplasms; Phagocytes; T-Lymphocytes; Thymosin

We recently identified an additional isoform of human thymosin beta 15 (also known as NB-thymosin beta, gene name TMSB15A) transcribed from an independent gene, and designated TMSB15B. The purpose of this study was to investigate whether these isoforms were differentially expressed and functional. Our data show that the TMSB15A and TMSB15B isoforms have distinct expression patterns in different tumor cell lines and tissues. TMSB15A was expressed at higher levels in HCT116, DU145, LNCaP, and LNCaP-LN3 cancer cells. In MCF-7, SKOV-3, HT1080, and PC-3MLN4 cells, TMSB15A and TMSB15B showed approximately equivalent levels of expression, while TMSB15B was the predominant isoform expressed in PC-3, MDA-MB-231, NCI-H322, and Caco-2 cancer cells. In normal human prostate and prostate cancer tissues, TMSB15A was the predominant isoform expressed. In contrast, normal colon and colon cancer tissue expressed predominantly TMSB15B. The two gene isoforms are also subject to different transcriptional regulation. Treatment of MCF-7 breast cancer cells with transforming growth factor beta 1 repressed TMSB15A expression but had no effect on TMSB15B. siRNA specific to the TMSB15B isoform suppressed cell migration of prostate cancer cells to epidermal growth factor, suggesting a functional role for this second isoform. In summary, our data reveal different expression patterns and regulation of a new thymosin beta 15 gene paralog. This may have important consequences in both tumor and neuronal cell motility.

Topics: Base Sequence; Cell Line, Tumor; Cell Movement; Data Interpretation, Statistical; Gene Expression Regulation, Neoplastic; Humans; Molecular Sequence Data; Neoplasms; Protein Isoforms; RNA Interference; Sequence Alignment; Thymosin; Transforming Growth Factor beta1

Topics: Actins; Antineoplastic Agents; Humans; Neoplasms; Thymosin

Topics: Animals; Cell Movement; Clinical Trials as Topic; Corneal Injuries; Eye Injuries; Humans; Myocardial Infarction; Neoplasms; Neovascularization, Physiologic; Thymalfasin; Thymosin; Wound Healing

Prothymosin alpha (proTalpha) is a 109 amino acid long polypeptide presenting distinct immunoenhancing activity in vitro and in vivo. Recent reports suggest that in apoptotic cells, proTalpha is cleaved by caspases at its carboxy(C)-terminus generating potentially bioactive fragments. In this study, we identified the peptide segment of proTalpha presenting maximum immunomodulatory activity. Calf thymus proTalpha was trypsinised, and the five fragments produced (spanning residues 1-14, 21-30, 31-87, 89-102 and 103-109) were tested for their ability to stimulate healthy donor- and cancer patient-derived peripheral blood mononuclear cell (PBMC) proliferation in autologous mixed lymphocyte reaction (AMLR), natural killer and lymphokine-activated killer cell activity, intracellular production of perforin, upregulation of adhesion molecules and CD25 expression. ProTalpha(89-102) and proTalpha(103-109) significantly fortified healthy donor-lymphocytes' immune responses to levels comparable to those induced by intact proTalpha. These effects were more pronounced in cancer patients, where peptides proTalpha(89-102) and proTalpha(103-109) partly, however significantly, restored the depressed AMLR and cytolytic ability of PBMC, by simulating the biological activity exerted by intact proTalpha. ProTalpha(1-14), proTalpha(21-30) and proTalpha(31-87) marginally upregulated lymphocyte activation. This is the first report showing that proTalpha's immunomodulating activity can be substituted by its C-terminal peptide(s). Whether generation and externalization of such immunoactive proTalpha fragments occurs in vivo, needs further investigation. However, if these peptides can trigger immune responses, they may eventually be used therapeutically to improve some PBMC functions of cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Animals; Binding Sites; Cattle; Chromatography, High Pressure Liquid; Female; Humans; Immunophenotyping; In Vitro Techniques; Leukocytes, Mononuclear; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Molecular Sequence Data; Neoplasms; Peptide Fragments; Protein Precursors; Sequence Homology, Amino Acid; Thymosin

Topics: Apoptosis; Caspase 3; Caspase 9; Caspases; Cell Transformation, Neoplastic; Enzyme Activation; Humans; Mitochondria; Neoplasms; Protein Precursors; Pyridines; RNA Interference; Thymosin; Tumor Suppressor Proteins

To investigate the effect of thymosin alpha 1 on cellular immune function in the elderly patients with malignant tumor.. Thirty patients with malignant tumor were injected with thymosin alpha 1 subcutaneously at the dose of 1.6 mg q.d. for the first month and q.o.d. for the following month. The number of T cell subgroups and the activity of NK cell in peripheral blood were detected and the quality of life of the patients were evaluated before treatment and at the end of treatment.. Treatment of thymosin alpha 1 increased the number of CD4 cells and improved the NK activity, and also improved the quality of life of the elderly patients with malignant tumor. There were no side effects found.. Thymosin alpha 1 can enhance the cellular immune function of the elderly patients with malignant tumor.

Topics: Aged; Aged, 80 and over; CD4 Lymphocyte Count; Female; Humans; Killer Cells, Natural; Male; Neoplasms; Quality of Life; Thymalfasin; Thymosin

The beta-thymosins comprise a family of structurally related, highly conserved acidic polypeptides, originally isolated from calf thymus. Recently, we have demonstrated the overexpression of thymosin beta-10 (TB10) in rat thyroid transformed cell lines and in human thyroid carcinoma tissues and cell lines. To verify whether TB10 overexpression is a general event in the process of carcinogenesis, we have analyzed TB10 mRNA levels in human colon carcinomas, germ cell tumors of different histological types, breast carcinomas, ovarian carcinomas, uterine carcinomas, colon and esophageal carcinoma cell lines. Overexpression of the TB10 gene was detected in all of the neoplastic tissues and cell lines compared to the respective normal tissues. Moreover, the mouse model of skin carcinogenesis induced by the combined action of chemical carcinogens and phorbol esters was used to identify the stage of TB10 gene induction. The expression was almost undetectable in normal keratinocytes, its induction occurred even at the papilloma stage, however a further increased expression was observed in the carcinoma derived cell lines. Finally, immunohistochemical analysis of some breast, colon and ovary carcinoma samples by using specific anti-TB10 antibodies revealed the presence of the TB10 protein in all of the neoplastic tissues, but not in the respective normal tissues. Therefore the TB10 detection may be considered a potential tool for the diagnosis of several human neoplasias.

Topics: Animals; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Esophageal Neoplasms; Female; Gene Expression; Germinoma; Humans; Immunohistochemistry; Male; Mice; Neoplasms; Ovarian Neoplasms; RNA; Skin Neoplasms; Testicular Neoplasms; Thymosin; Tumor Cells, Cultured; Uterine Neoplasms

We reported that tumor content of prothymosin alpha (ProT alpha) is a proliferation index of human breast tumors that might be used to identify patients at high risk for distant metastasis (Dominguez et al., Eur J Cancer 1993; 29A:893-7). In that study ProT alpha concentrations were measured by a RIA; here we present an alternative nonisotopic assay that could be used in a standard clinical laboratory. Main features of the ELISA are: (a) A recombinant fusion protein glutathione S-transferase (GST)-human ProT alpha was used to coat the microtiter plates; (b) we used a polyclonal antiserum raised in rabbits that detects thymosin alpha1, the NH2-terminal fragment of ProT alpha; (c) it is as sensitive as the RIA; (d) it is faster than the RIA. ProT alpha concentrations in various human tumors (skin, esophagus, colorectal, and breast) as assessed by ELISA were comparable with, although twofold greater than, the values previously estimated by RIA.

Topics: Antibody Specificity; Enzyme-Linked Immunosorbent Assay; Humans; Immune Sera; Neoplasms; Peptide Fragments; Protein Precursors; Regression Analysis; Sensitivity and Specificity; Thymalfasin; Thymosin

Radioimmunoassays specific for the N and C termini of human prothymosin alpha and the N terminus of human parathymosin alpha were employed for the measurement of the levels of alpha-thymosins in human thymus, spleen, and liver during normal growth and intestine and breast in malignant growth. A differential expression of the two alpha-thymosins was observed in thymus (prothymosin alpha-rich) and liver (parathymosin alpha-rich). A decline in the levels of both alpha-thymosins was found with age, with prothymosin alpha in thymus showing the sharpest change (15- to 30-fold). The levels of both alpha-thymosins were higher in malignant tissues as compared with healthy ones. In breast cancer, in particular, the mean increase for prothymosin alpha and parathymosin alpha was 17.9- and 11.5-fold, respectively. The major crossreactive material was characterized in all cases as intact prothymosin alpha and parathymosin alpha. These results suggest an in vivo relationship of the expression of alpha-thymosins with the human tissue cell proliferation activity.

Topics: Adolescent; Adult; Age Factors; Aged; Cell Division; Child; Child, Preschool; Humans; Infant; Liver; Middle Aged; Neoplasms; Radioimmunoassay; Thymosin; Thymus Gland

Cancer-bearing patients exhibit a variety of profound T-cell abnormalities which include decreased cytotoxic capacity as measured by allogeneic cell-mediated lympholysis (CML), natural-killer (NK) cell activity, and decreased lymphokine production. In patients with advanced solid malignancies, allogeneic CML, tested by a 4-hr 51Cr-release assay, was significantly lower than in a group of normal individuals. If optimal doses of affinity-purified prothymosin alpha (ProT alpha) were present during mixed lymphocyte culture, the CML of cancer patients was increased almost to normal levels. Mixed lymphocyte reaction, tested by tritiated thymidine uptake, was also decreased in these patients and was enhanced to normal levels if ProT alpha was added to the cultures. NK activity was decreased in these patients according to 51Cr-release assays. ProT alpha increased the NK activity up to normal levels. The reduced NK and CML activities in cancer patients were associated with abnormal production of prostaglandin E2 (high) and interleukin-2 (low), which were to a great extent normalized in the presence of ProT alpha. These results demonstrate that ProT alpha is capable of potentiating or fully restoring the deficient cytotoxic effector function of peripheral mononuclear cells (MNC) in patients with advanced malignancies.

Topics: Adult; Aged; Aged, 80 and over; Cytotoxicity, Immunologic; Dinoprostone; Female; Humans; In Vitro Techniques; Interleukin-2; Killer Cells, Natural; Lymphocyte Culture Test, Mixed; Lymphocytes; Male; Middle Aged; Neoplasms; Protein Precursors; Thymosin

Topics: Aging; Animals; Immune System; Incidence; Longevity; Male; Mice; Mice, Inbred Strains; Neoplasms; Peptide Fragments; Thymalfasin; Thymosin

Advances in the treatment of limited small-cell lung cancer (L-SCLC) have led to improved short-term outcome. However, it is not clear how well this predicts the ultimate fate of the patients. This may be affected by late relapse of SCLC, the development of second malignancies, and the long-term toxicity of therapy. To address this issue we report follow-up in excess of 5 years on a cohort of 36 patients who had high short-term survival resulting from treatment with chemotherapy combined with cranial and thoracic irradiation. All patients were followed until death or the time of analysis. The initially promising result of 31% survival at 3 years, was reflected in survival from SCLC of 27% at 5 years, and 23% at 9 years. However, when death from all causes was analyzed, survival was only 19% at 5 years and 7% at 9 years. There were 2 survivors disease-free at 7 and 8 years; 7 patients died of other causes without any evidence of SCLC. Among those not dying of SCLC, 4 patients developed second malignancies with a risk of 22% at 3.2 years and 50% at 8 years. Clinical neurotoxicity developed in 3 patients. These data suggest that cure of SCLC is possible in a modest proportion of patients with limited disease, but that the survivors are at significant risk of developing second malignancies which emerge as the most common cause of death during prolonged follow-up. Successful outcome of treatment is further hampered by the occurrence of neurotoxicity. Clinical strategies to prevent these sequelae of therapy are discussed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasms; Predictive Value of Tests; Radiotherapy; Risk Factors; Survival Rate; Thymosin

Thymosins beta 4 and beta 10 are 2 structurally related polypeptides originally defined in the rat immune system. To date, no truly unambiguous functions have been formally ascribed to these small (less than 4.9 kDa) acidic proteins. Previous research has demonstrated relationships between expression of these genes and cell growth/differentiation. These observations prompted the present study which has used cDNA and synthetic oligonucleotide probes in combination with high-performance liquid chromatography (HPLC) to examine the differential expression of these 2 genes in normal and neoplastic human tissues and in the developing human kidney. Low levels of beta 4 and beta 10 mRNA species prevailed in normal tissues; in contrast, these gene transcripts were notably more abundant in malignant renal tumors and in the normal human embryonic kidney. These findings show that the thymosin beta 4 and beta 10 genes are constitutively expressed at higher levels in embryonic/neoplastic as compared to normal/benign tissues and that thymosin in beta 10 in particular may be a new molecular marker for renal-cell carcinoma as well as other malignancies.

Topics: Aging; Base Sequence; Blotting, Northern; Breast Neoplasms; Chromatography, High Pressure Liquid; Cloning, Molecular; Female; Gene Expression; Humans; Infant; Kidney; Kidney Neoplasms; Middle Aged; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Nucleic Acid Hybridization; Oligonucleotide Probes; Ovarian Neoplasms; Reference Values; RNA, Messenger; Thymosin

Previous Phase I trials have established the safety of administering thymosin fraction 5 and thymosin alpha 1 to patients with advanced cancer. These same trials also suggested potential immune-enhancing doses of these agents. In this study, 12 patients with colon cancer were treated with thrice weekly thymosin fraction 5 at a dose of 120 mg/m2, and 10 patients with non-small-cell lung cancer received thymosin alpha 1 at 1.2 mg/m2 thrice weekly. Five patients with hypernephroma also received one or both agents by a thrice weekly schedule. There were no tumor responses observed in any of these patients, and immune enhancement was neither obtained nor sustained. We conclude that at these doses and schedules, these hormones have very limited, if any, antitumor properties and that they are incapable of producing immune augmentation as defined by the assays used in this study.

Topics: Drug Evaluation; Female; Humans; In Vitro Techniques; Lymphocyte Activation; Male; Middle Aged; Neoplasms; Thymalfasin; Thymosin

An analysis of recently conducted phase I trials of biological response modifiers (BRM), performed mainly under the sponsorship of the BRM Program of the National Cancer Institute, has led to the development of a format for performing such trials with these agents in the future. The evolution of this format and its use in ongoing phase I trials of recombinant beta and gamma interferons is discussed. An evaluation of the method will be undertaken at the conclusion of these studies.

Topics: Biological Products; Carboxymethylcellulose Sodium; Drug Evaluation; Humans; Interferon Type I; Interferon-gamma; Neoplasms; Poly I-C; Polylysine; Thymosin

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Antigens, Neoplasm; BCG Vaccine; Humans; Immunization; Immunotherapy; Interferons; Lymphokines; Neoplasms; Thymosin

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Antigens, Neoplasm; Biological Products; Humans; Immunotherapy; Interferon Type I; Interferon-gamma; Interleukin-2; Lymphokines; Neoplasms; Thymosin

Topics: Acquired Immunodeficiency Syndrome; Animals; Humans; Immunotherapy; In Vitro Techniques; Interferon Type I; Interferon-gamma; Interferons; Killer Cells, Natural; Mice; Neoplasms; Phagocytosis; Thymosin

Since patients with advanced cancer are usually immunodeficient, they might benefit from therapy with thymic hormones, which have an immunorestorative effect in immunosuppressed laboratory animals. We treated 14 patients with thymosin fraction 5 (TF5), and 14 patients with thymosin alpha 1 (TA1) over the dose ranges of 60-960 mg/m2 and 0.6-9.6 mg/m2, respectively. In addition to monitoring toxicity, we studied patients extensively using a variety of lymphocyte cell surface markers and in vitro functional assays, both before and following treatment. Approximately one-half of the in vitro tests were abnormal in the cancer patients prior to treatment. Overall, 28.4 and 18.3% of abnormal tests were improved following TA1 and TF5, respectively. On the other hand, 16% of normal tests became abnormal after therapy. Most of these responses occurred within 24-48 h and seldom persisted beyond 72 h. An optimum dose of TF5 was not readily identified, but 1.2 mg/m2 of TA1 was associated with substantial improvement in 46% of abnormal tests. Twelve of 14 cancer patients who received TF5 and 13 of 14 who received TA1 showed significant improvement in at least one in vitro test. Tumor responses were not seen, but the study suggested thymosin treatments would need to be repeated every 2-3 days to sustain an immune response. TF5 and TA1 are well tolerated as single i.m. injections, and have immunorestorative potential in cancer patients. Additional studies with repeated thymosin doses in more homogeneous cancer populations appear to be justified.

Topics: Female; Herpesvirus 3, Human; Humans; Immunity; Lymphocytes; Male; Middle Aged; Neoplasms; Thymalfasin; Thymosin; Time Factors

Topics: Animals; Cattle; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Neoplasms; Rosette Formation; T-Lymphocytes; Thymosin; Thymus Hormones

The effect of iv injection in C57BL/6 mice of 3X10(7) bone marrow cells preincubated in either thymosin fraction V or thymosin alpha-1 was evaluated on the growth of a 3-methylcholanthrene-induced transplantable tumor in a syngeneic system. The effect was then compared to that elicited by theophylline or levamisole, which both demonstrated thymosin-like action in vitro. The results showed significantly retarded tumor growth (P less than 0.001) and prolonged survival time (P less than 0.001) when thymosin fraction V was used. The same results were obtained with thymosin alpha-1 with use of the same protocol but only one-twentieth of the concentration of fraction V. Theophylline and levamisole demonstrated no antitumor effect.

Topics: Animals; Bone Marrow Transplantation; Cell Division; Levamisole; Male; Methylcholanthrene; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms; Theophylline; Thymosin; Thymus Hormones; Time Factors

Thymosin fraction 5 contains a family of polypeptides with varying biological activities. Current efforts in the thymosin research program are involved in further chemical characterization of thymosin peptides and evaluation of clinical immunotherapeutic protocols. Recent clinical studies with thymosin fraction 5 have shown therapeutic potentials for treatment of patients with primary immunodeficiency diseases and cancer.

Topics: Cyclic GMP; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; Neoplasms; Thymosin; Thymus Hormones

We have demonstrated that splenic lymphocytes from normal syngeneic animals can stimulate tumor growth. This effect is T-cell dependent. Preincubation of these lymphocytes with thymosin not only blocks facilitated tumor growth but can induce a significant reduction of local tumor growth and number of pulmonary metastases. Furthermore, thymosin can also block the expression of suppressor activity of lymphocytes either stimulated by Con A or originating from various advanced solid tumor bearing patients. These results therefore suggest that thymosin is able to modulate, directly or indirectly, functional expression of suppressor cells.

Topics: Animals; Humans; In Vitro Techniques; Lymphocytes; Mice; Neoplasms; Neoplasms, Experimental; Rosette Formation; T-Lymphocytes, Regulatory; Thymosin; Thymus Hormones

Topics: Erythrocytes; Humans; Neoplasms; Rosette Formation; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Adolescent; Adult; Aged; Carcinoembryonic Antigen; Carcinoma, Bronchogenic; Female; Fibronectins; Humans; Immunotherapy; Leukocyte Count; Lung Neoplasms; Male; Middle Aged; Neoplasms; Smoking; T-Lymphocytes; Thymosin; Thymus Hormones; Time Factors

Topics: Humans; Immunotherapy; Interferons; Lymphokines; Neoplasms; Thymosin

We have identified the presence of suppressor cell activity in the peripheral blood of immunosuppressed stage IV cancer patients. The patients' cells had a diminished mitogenic response to phytohemagglutinin (PHA) and suppressed the PHA mitogenic response of a normal donor's peripheral blood lymphocytes (PBL). Thus, PBL from a cancer patient whose PHA mitogenic response was 3932 counts per minute (cpm), cultured together with a normal donor's PBL with a PHA mitogenic response of 82,865 net cpm, caused a greater than 50% reduction in the latter (37,651 net cpm). Suppressor cell activity was present in 12 of 14 patients tested. This effect was partially mitigated by irradiation with 4000 rads in nine of 14 patients. Preincubation of the patients' cells with thymosin followed by the addition of thymosin to the co-cultured cells mitigated the suppressor activity in five of ten patients and thymic humoral factor did the same in four of 11 patients. A radiosensitive and thymic hormone-responsive suppressor cell may be present in the peripheral blood of cancer patients. Confirmation of this preliminary observation and further characterization of the cell or cells is currently being undertaken.

Topics: Female; Humans; Immunosuppression Therapy; In Vitro Techniques; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Male; Neoplasms; Phytohemagglutinins; Thymosin; Thymus Hormones

Our current research program centers around the biologic and chemical characterization of the family of polypeptides present in thymosin fraction 5. A system of nomenclature has been developed and the peptides are being systematically isolated and chemically characterized. Thymosin fraction 5 and its component parts influence a variety of lymphocyte properties including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production, and expression of certain surface markers. Thymosin is being used in clinical trials to investigate its effects on immunodeficiency diseases, malignant diseases, and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Chemical Phenomena; Chemistry; Cyclic AMP; Cyclic GMP; Drug Evaluation; Guinea Pigs; Humans; Immunologic Deficiency Syndromes; In Vitro Techniques; Lymphocytes; Neoplasms; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Adenocarcinoma; Animals; BCG Vaccine; Bronchial Neoplasms; Colonic Neoplasms; Corynebacterium Infections; Humans; Immunotherapy; Levamisole; Melanoma; Neoplasms; Propionibacterium acnes; RNA, Neoplasm; Sheep; Thymosin

Topics: Adult; B-Lymphocytes; Breast Neoplasms; Dose-Response Relationship, Immunologic; Humans; Kidney Neoplasms; Melanoma; Middle Aged; Neoplasms; Rosette Formation; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Chemical Phenomena; Chemistry; Humans; Immunologic Deficiency Syndromes; Neoplasms; Thymosin; Thymus Hormones

Topics: Adult; Animals; Cattle; Child; Culture Media; Female; Fetal Blood; Humans; Hypersensitivity, Immediate; In Vitro Techniques; Neoplasms; Pregnancy; Rosette Formation; T-Lymphocytes; Thymosin; Thymus Hormones

A Phase I clinical trial of thymosin administered in doses of 10 to 250 mg/M2 intramuscularly for seven days was undertaken in ten patients with disseminated malignancies and evidence of immunoincompetence. Toxicity was minimal; one patient experienced a mild urticarial rash which cleared spontaneously, two patients developed low grade fever and one patient experienced pain at the injection site. There was no evidence of systemic toxicity or parenchymal organ dysfunction. Thymosin administration was associated with an increase in the E-rosette forming capacity of the patient's lymphocytes and the development of new skin test reactivity to recall antigens in some of these patients. One objective tumor response was noted. These findings are preliminary but are encouraging for further utilization of thymosin as an immunostimulant in cancer patients with immunoincompetence.

Topics: Adenocarcinoma; Breast Neoplasms; Drug Eruptions; Dysgerminoma; Hodgkin Disease; Humans; Immune Adherence Reaction; Immunity, Cellular; Leiomyosarcoma; Lung Neoplasms; Lymphocytes; Melanoma; Neoplasm Metastasis; Neoplasms; Skin Tests; Thymosin; Thymus Hormones

Thymosin, a soluble extract of fetal calf thymus, has increased cellular immunity in children with thymic deficiency. Prior to therapy, an increase in thymus-dependent lymphocyte (T cell) levels in vitro after incubation with thymosin correlated with a rise in peripheral blood T cell levels and improvement in other parameters of cellular immunity. These correlations constituted the basis for a study of the effects of thymosin on T cell levels in vitro in cancer patients. Groups studied were 350 untreated patients with local-regional solid malignancies, 157 patients cured of these tumors, 340 patients studied at 523 intervals during radiation therapy, 80 patients receiving chemotherapy for disseminated solid malignancies, and 427 normal volunteers. Although there were significant differences among the groups in mean leukocyte, lymphocyte and T cell levels, among those with low T cell levels in each group there was a significant inverse relation between T cell levels after incubation with thymosin in vitro and initial T cell levels, with the exception of patients receiving chemotherapy. In patients receiving chemotherapy, T cell levels increased independently of initial T cell levels. These in vitro observations are consistent with evidence that a major effect of thymosin is maturation of T cell precursors; however, the effect is that of reconstitution at low T cell levels, and not of elevation to levels significantly above normal. The results provide a rationale for clinical trials with thymosin to maintain immune competence during radiation therapy and chemotherapy, and for a two-phase approach to immunotherapy of cancer utilizing thymosin for reconstitution of cellular defects followed by administration of agents that potentiate cellular immunity.

Topics: Adolescent; Adult; Aged; Child; Female; Humans; Immunity, Cellular; Immunotherapy; In Vitro Techniques; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasms; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Humans; Immunologic Deficiency Syndromes; Immunologic Techniques; Neoplasms; Thymosin; Thymus Hormones

Topics: Animals; Cattle; Europe; History, 19th Century; History, 20th Century; History, Ancient; Humans; Immunologic Deficiency Syndromes; Mice; Neoplasms; T-Lymphocytes; Thymectomy; Thymosin; Thymus Gland; Thymus Hormones; United States

The effect of thymosin in vitro on percent T cells was determined in 388 blood specimens from patients with head and neck, mediastinal, and pelvic malignancies during radiation therapy, in 94 untreated patients with these malignancies, and 277 normal adults. Changes in percent T cell levels after incubation of lymphocytes with thymosin did not correlate with tumor histology or cumulative radiation dose, but in all groups correlated with radiation portal and initial T cell levels. T cell levels increased by a similar increment in normals and in the untreated patients. During irradiation, the mean levels after incubation with thymosin did not change in patients with head and neck and pelvic malignancies, but in patients with mediastinal malignancies the levels increased significantly more than in normals. For a given T cell level, the increase in patients with mediastinal malignancies was greater than in patients with pelvic malignancies, and as a group was greater than in patients with head and neck malignancies. The results can be explained by an increase in circulating thymosin-responsive lymphocytes during mediastinal irradiation due to suppression of a function of the thymus important for maturation of these cells, and a decrease in these cells during pelvic irradiation due to a deleterious effect on precursors in pelvic bone marrow. The results thus provide a rationale for clinical trials to assess the efficacy of thymosin in averting declines of T cell levels in patients receiving mediastinal irradiation.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Radiation; Female; Head and Neck Neoplasms; Humans; In Vitro Techniques; Leukocyte Count; Male; Mediastinal Neoplasms; Middle Aged; Neoplasms; Pelvic Neoplasms; Radiotherapy Dosage; Radiotherapy, High-Energy; T-Lymphocytes; Thymosin; Thymus Hormones

Topics: Animals; Child; Humans; Immunotherapy; Mice; Neoplasms; Thymosin; Thymus Hormones

Topics: Animals; Child; Child, Preschool; Female; Humans; Hypersensitivity, Delayed; Immune Adherence Reaction; Immunity, Cellular; Immunologic Deficiency Syndromes; Infant; Lymphocyte Culture Test, Mixed; Lymphocytes; Male; Mice; Mice, Inbred Strains; Mitogens; Neoplasms; Thymosin; Thymus Extracts

Thymosin, fraction V, prepared by the method of Goldstein et al., was studied in in vitro lymphocyte cultures with cells obtained from normal subjects and patients with disseminated cancer. Thymosin lowered blastogenic activity in some patients, did not affect it in others, and increased counts in still others. There was a statistically significant depression in baseline (prethymosin) counts from both normals and patients when individuals whose counts increased in the presence of thymosin were compared with other subjects. We conclude that thymosin tended to raise depressed blastogenesis into the normal range without causing supranormal activity or without itself acting as a mitogen or antigen. Eighty-two in vivo courses in thymosin were given to 32 patients. Analysis of the first thymosin courses in these 32 patients shows that immunologic reconstitution occurred in patients with originally depressed T-cell function and numbers, whereas little change was apparent in patients with initially intact tests of T-cell activity. Clinical effects were equivocal; however, no systematic clinical trial was conducted. Toxicity was minimal (four of the 32 patients); in each case, it consisted of inflammation at the injection site. The in vitro and in vivo results of this study suggest that thymosin therapy modulates and partially normalizes T-lymphocyte numbers and function.

Topics: Humans; Immunity, Cellular; Immunologic Techniques; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocytes; Neoplasms; Skin Tests; T-Lymphocytes; Thymidine; Thymosin; Thymus Hormones

The effect of thymosin on in vitro reactivity of peripheral lymphocytes to phytohemagglutinin, concanavalin A, and the formation of spontaneous E-rosettes in 54 patients with metastatic carcinomas has been studied. Thymosin increased lymphocyte responses to PHA and Con A in only 10 patients, with predominant effect seen with Con A. Twenty patients showed depressed baseline levels of E-rosettes which were increased to normal or subnormal levels after incubation with thymosin. No distinct correlation was noted between the clinical stage of the disease and the ability of lymphocytes to form E-rosettes. Although the exact mechanism by which the thymus exerts its influence on host resistance is not clearly defined, present evidence supports the concept that the thymic hormone, thymosin, may be an important addition in treatment of cancer patients by increasing cell-mediated immunity.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Carcinoma, Bronchogenic; Concanavalin A; Hodgkin Disease; Humans; Immune Adherence Reaction; In Vitro Techniques; Lectins; Middle Aged; Neoplasms; T-Lymphocytes; Thymosin; Thymus Extracts

Topics: Age Factors; Animals; Cell Differentiation; Dogs; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; Lupus Erythematosus, Systemic; Mice; Molecular Weight; Neoplasms; T-Lymphocytes; Thymosin; Thymus Extracts

Thymosin, a thymic hormone, restores decreased cellular immunity under various experimental conditions. The purpose of this study was to evaluate the effect of thymosin on the E-rosette-forming capacity in cancer patients. Peripheral blood lymphocytes obtained from eight patients with various malignant neoplasms were examined. One of these patients received thymosin intramuscularly; his E-rosette formation was examined serially. Eight normal adults served as controls. Patients with advanced stages of malignant tumors showed decreased E-rosette-forming capacity, which increased significantly under the influence of thymosin. Patients with less-advanced tumors, as well as normal adults, demonstrated normal E-rosette formation without further effects by thymosin. The in vivo administration of thymosin to one patient was followed by a marked increase of the E-rosette-forming capacity. These results suggest that the administration of thymosin, both in vivo and in vitro, significantly increases the circulating T-lymphocyte levels and/or functions in patients with advanced malignant neoplasms.

Topics: Adult; Aged; Humans; Immune Adherence Reaction; Lymphocytes; Middle Aged; Neoplasms; Thymosin; Thymus Extracts