thymalfasin and Lung-Neoplasms

Thymosin α1 (Tα1) is a naturally occurring polypeptide that regulates immune cell development and function, and is also capable of interacting with multiple target cells with relevant biological effects. The rationale of Tα1 use in cancer treatment stems from the consideration that tumor progression is favored by a failure of the immune response and in turn induces immune suppression. This paper will review the historical background of Tα1 use in oncology, aiming to highlight the importance of Tα1 as an immunotherapeutic tool to be used in combination with chemotherapy, a concept that is not yet fully established in clinic.. The efficacy and safety of combining Tα1 with chemotherapy and cytokines were first evaluated in murine tumor models, providing essential information about effects, mechanisms of action, doses and treatment protocols. The therapeutic potential of the chemo-immunotherapy protocol on metastatic melanoma and lung cancer has been confirmed in controlled clinical trials. Critical for the efficacy of the chemo-immunotherapy protocol is the dual action of Tα1 on immune effector and tumor cells.. On the basis of the preclinical and clinical results available, the use of the chemo-immunotherapy protocol, in which the role of Tα1 is central, is strongly recommended.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Cytokines; Drug Evaluation, Preclinical; Humans; Immunotherapy; Lung Neoplasms; Melanoma; Thymalfasin; Thymosin

Using a partially purified preparation, thymosin fraction 5, we have documented that thymosin can correct many of the immunological deficiencies resulting from the lack of thymosin function in animal models and in humans. Ongoing studies indicate that there is a family of biologically active peptides within fraction 5 that act on T-cell subpopulations to maintain normal immunological reactivity. Several of these peptides have been purified to homogeneity. Two peptides, thymosin alpha 1 and beta 4, have been sequenced and chemically synthesized. Thymosin fraction 5 has been used in most clinical trials reported to date, including children with immunodeficiency disease and patients with autoimmune diseases and cancer. Most recently, the National Cancer Institute has initiated a number of Phase I and Phase II clinical trials with thymosin fraction 5 and synthetic alpha 1 as part of a new Biological Response Modifier Program. Preliminary results from two of these studies look encouraging.

Topics: Amino Acid Sequence; Animals; Autoimmune Diseases; Carcinoma, Small Cell; Cattle; Clinical Trials as Topic; Isoelectric Focusing; Lung Neoplasms; Macrophage Migration-Inhibitory Factors; Molecular Weight; Peptides; T-Lymphocytes; T-Lymphocytes, Regulatory; Terminology as Topic; Thymalfasin; Thymosin

A phase II study was performed to evaluate the clinical and immunological effects of a regimen of cisplatin (DDP) and etoposide (VP-16) combined with thymosin-alpha 1 (TA1) and low-dose interferon-alpha 2a (IFN) in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemoimmunotherapy cycles were repeated every 3 weeks. There were 24 responses (two complete, 22 partial) among 56 assessable patients. Median survival was 12.6 months. Overall, treatment was well tolerated. Natural killer cell activity and lymphocyte subtypes were depressed by chemotherapy, but this effect was less prominent in patients receiving TA1 and IFN in comparison with a concomitant group of patients treated with DDP and VP-16 only. The combination of DDP and VP-16 and TA1 and IFN is effective in advanced NSCLC with acceptable toxicity. However, the results of this study need to be confirmed in a randomised trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Combined Modality Therapy; Etoposide; Female; Humans; Interferon alpha-2; Interferon-alpha; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins; Remission Induction; Survival Analysis; Thymalfasin; Thymosin

The effects of mediastinal irradiation (RT) on the numbers and functions of purified peripheral blood T-lymphocytes from patients with locally advanced non-small cell lung cancer were evaluated. The patients were candidates for a randomized trial to evaluate the immunorestorative properties of synthetic thymosin alpha-1. Twenty-one patients studied before RT did not exhibit any significant difference in T-cell numbers or function compared to age-matched healthy subjects. However, 41 patients studied within 1 week after completing RT exhibited significant depressions of E-rosette-forming cells at 4 degrees C (E4 degrees-RFC)/mm3, E-rosette-forming cells at 29 degrees C (E29 degrees-RFC)/mm3, OKT3/mm3, OKT4/mm3, and OKT8/mm3 (P = 0.0001); total T-cell percentages (%OKT3, P = 0.01); and T-cell proliferative responses in mixed lymphocyte cultures (MLR) (P = 0.01) and to the mitogen phytohemagglutinin under suboptimal conditions (P less than or equal to 0.03). Nine patients studied before and after RT showed a significant increase in OKT4/OKT8 (P = 0.01) following RT. A short-term in vitro incubation with thymosin alpha-1 could enhance MLR of T-cells in 12 of 27 patients with post-RT abnormalities. In 13 patients who were treated with placebo, the RT-induced depression of T-cell numbers and function persisted for at least 3 to 4 months. In addition, in 12 patients progressive decreases developed in %E4 degrees-RFC, %OKT3, %OKT4, and OKT4/OKT8, which always preceded clinical relapse. This study indicates that mediastinal RT results in prolonged depletion of circulating T-cells, alterations of T-cell subset proportions, and intrinsic T-cell functional deficiencies. This patient population provides a uniformly immunosuppressed group of subjects with which to evaluate the immunorestorative effects of thymosin alpha-1 or other biologic response modifiers.

Topics: Adult; Aged; Female; Humans; In Vitro Techniques; Lung Neoplasms; Lymphocyte Culture Test, Mixed; Male; Mediastinum; Middle Aged; Radiotherapy; T-Lymphocytes; Thymalfasin; Thymosin

A randomized trial was performed in 42 postradiotherapy patients with non-small cell lung cancer to determine whether the administration of synthetic thymosin-alpha 1 by either a loading dose or a twice-weekly schedule could accelerate the reconstitution of thymic dependent immunity. The radiotherapy-induced immunosuppression was characterized by an absolute T cell lymphopenia and by impaired T cell function in lymphoproliferative assays. Placebo-treated patients did not show any improvement in T cell numbers or function over 15 weeks of serial immune monitoring, and exhibited gradual depressions of helper T lymphocyte percentages. Patients treated with thymosin by the loading dose regimen exhibited a normalization of T cell function (p = 0.04), whereas patients treated with the twice-weekly schedule maintained normal helper T cell percentages (p = 0.04). Thymosin treatment was associated with significant improvements in relapse-free and overall survival, which was most pronounced for patients with nonbulky tumors. Thymosin-alpha 1 exhibits schedule-dependent immune restorative and homeostatic properties. Large scale Phase III trials are indicated to definitively establish the impact of thymosin therapy in lung cancer patients treated with radiotherapy.

Topics: Adjuvants, Immunologic; Aged; Drug Evaluation; Female; Humans; Immunity, Cellular; Immunosuppression Therapy; Lung Neoplasms; Male; Middle Aged; Radiation Injuries; Random Allocation; Thymalfasin; Thymosin

Using a partially purified preparation, thymosin fraction 5, we have documented that thymosin can correct many of the immunological deficiencies resulting from the lack of thymosin function in animal models and in humans. Ongoing studies indicate that there is a family of biologically active peptides within fraction 5 that act on T-cell subpopulations to maintain normal immunological reactivity. Several of these peptides have been purified to homogeneity. Two peptides, thymosin alpha 1 and beta 4, have been sequenced and chemically synthesized. Thymosin fraction 5 has been used in most clinical trials reported to date, including children with immunodeficiency disease and patients with autoimmune diseases and cancer. Most recently, the National Cancer Institute has initiated a number of Phase I and Phase II clinical trials with thymosin fraction 5 and synthetic alpha 1 as part of a new Biological Response Modifier Program. Preliminary results from two of these studies look encouraging.

Topics: Amino Acid Sequence; Animals; Autoimmune Diseases; Carcinoma, Small Cell; Cattle; Clinical Trials as Topic; Isoelectric Focusing; Lung Neoplasms; Macrophage Migration-Inhibitory Factors; Molecular Weight; Peptides; T-Lymphocytes; T-Lymphocytes, Regulatory; Terminology as Topic; Thymalfasin; Thymosin

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: Adjuvants, Immunologic; Clinical Trials as Topic; Humans; Immunologic Deficiency Syndromes; Lung Neoplasms; Thymalfasin; Thymosin; Thymus Hormones

Thymosin alpha 1 (Tα1) is a highly conserved 28 amino-acid peptide naturally occurring in the thymus and plays critical roles in T cell maturity and differentiation. Its synthetic form, thymalfasin, has been approved by various regulatory agencies in the treatment of hepatitis B viral infection and as an enhancer of vaccine response in immune-compromised populations. In China, it has also widely utilized in patients with cancer and severe infections, as well as the emergency use during (Severe Acute Respiratory Syndrome)SARS and COVID-19 pandemic as an immune-regulator. Recent studies showed that Tα1 could significantly improve overall survival (OS) in patients with surgically resectable non-small cell lung cancer (NSCLC) and liver cancers in the adjuvant setting. For patients with locally advanced, unresectable NSCLC, Tα1 could significantly reduce chemoradiation-induced lymphopenia, pneumonia, and trending improvement of OS. Preclinical evidence are emerging to demonstrate that Tα1 may augment efficacy of cancer chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis and enhancing anti-tumor immunity by turning "cold-tumors" to "hot-tumors"; a protective role in reducing colitis caused by immune check-point inhibitors (ICIs). Potential enhancement of ICIs' clinical efficacies has also been indicated. ICIs have transformed ways treating patients with cancer but limitations such as relatively low response rates and certain safety issues remains. Given the roles of Tα1 in regulating cellular immunities and exceptional safety profiles demonstrated in decades clinical uses, we believe that it is plausible to explore implications of Tα1 the immune-oncology setting by combining with ICI-based therapeutic strategies. Background Activities of Tα1. Tα1 is a biological response modifier which activates various cells in the immune system [1-3]. Tα1 is therefore expected to have clinical benefits in disorders where immune responses are impaired or ineffective. These disorders include acute and chronic infections, cancers, and vaccine non-responsiveness. In severe sepsis, for example, sepsis-induced immunosuppression is increasingly recognized as the overriding immune dysfunction in these vulnerable patients [4] and there is now agreement that many patients with severe sepsis survive the first critical hours of the syndrome but eventually die later due to patients' immunosuppression which make the system diff

Topics: Carcinoma, Non-Small-Cell Lung; COVID-19; Humans; Lung Neoplasms; Pandemics; Sepsis; Thymalfasin; Thymosin

There is limited information about thymosin α1 (Tα1) as adjuvant immunomodulatory therapy, either used alone or combined with other treatments, in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the effect of adjuvant Tα1 treatment on long-term survival in margin-free (R0)-resected stage IA-IIIA NSCLC patients.. A total of 5746 patients with pathologic stage IA-IIIA NSCLC who underwent R0 resection were included. The patients were divided into the Tα1 group and the control group according to whether they received Tα1 or not. A propensity score matching (PSM) analysis was performed to reduce bias, resulting in 1027 pairs of patients.. After PSM, the baseline clinicopathological characteristics were similar between the two groups. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly higher in the Tα1 group compared with the control group. The multivariable analysis showed that Tα1 treatment was independently associated with an improved prognosis. A longer duration of Tα1 treatment was associated with improved OS and DFS. The subgroup analyses showed that Tα1 therapy could improve the DFS and/or OS in all subgroups of age, sex, Charlson Comorbidity Index (CCI), smoking status, and pathological tumor-node-metastasis (TNM) stage, especially for patients with non-squamous cell NSCLC and without targeted therapy.. Tα1 as adjuvant immunomodulatory therapy can significantly improve DFS and OS in patients with NSCLC after R0 resection, except for patients with squamous cell carcinoma and those receiving targeted therapy. The duration of Tα1 treatment is recommended to be >24 months.

Topics: Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Humans; Immunomodulation; Lung Neoplasms; Neoplasm Staging; Propensity Score; Retrospective Studies; Thymalfasin

Thymosin alpha-1 (TA) has been reported to inhibit tumor growth as an immunomodulator. However, its mechanism of action in immunosuppressive cells is unclear. The purpose of this study was to investigate whether TA can reshape the immune microenvironment by inhibiting the function of myeloid-derived suppressor cells (MDSCs) in non-small cell lung carcinoma (NSCLC).. The effects of TA on peripheral blood monocytic MDSCs (M-MDSCs) in patients with NSCLC and on the apoptosis and migration of M-MDSCs were studied. A mouse subcutaneous xenograft tumor model was constructed, and the effect of TA on M-MDSC migration was evaluated. Quantitative real-time PCR, Western blotting, flow cytometry and immunohistochemistry were used to examine the mechanism by which TA affects M-MDSCs.. TA not only promoted the apoptosis of M-MDSCs by reducing the Bcl-2/BAX ratio but also and more importantly inhibited the migration of MDSCs to the tumor microenvironment by suppressing the production of vascular endothelial growth factor (VEGF) through the downregulation of hypoxia-inducible factor (HIF)-1α in tumor cells.. TA may have a novel antitumor effect mediated by decreasing M-MDSC accumulation in the tumor microenvironment through reduced VEGF production.

Topics: A549 Cells; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Migration Inhibition; Cell Movement; Female; Humans; Lung Neoplasms; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; Thymalfasin; Vascular Endothelial Growth Factor A

Tumor-targeted therapy is an attractive strategy for cancer treatment. Peptide hormone thymosin α1 (Tα1) has been used against several diseases, including cancer, but its activity is pleiotropic. Herein, we designed a fusion protein Tα1-iRGD by introducing the tumor homing peptide iRGD to Tα1. Results show that Tα1-iRGD can promote T-cell activation and CD86 expression, thereby exerting better effect and stronger inhibitory against melanoma and lung cancer, respectively, than Tα1 in vivo. These effects are indicated by the reduced densities of tumor vessels and Tα1-iRGD accumulation in tumors. Moreover, compared with Tα1, Tα1-iRGD can attach more B16F10 and H460 cells and exhibits significantly better immunomodulatory activity in immunosuppression models induced by hydrocortisone. Circular dichroism spectroscopy and structural analysis results revealed that Tα1 and Tα1-iRGD both adopted a helical confirmation in the presence of trifluoroethanol, indicating the structural basis of their functions. These findings highlight the vital function of Tα1-iRGD in tumor-targeted therapy and suggest that Tα1-iRGD is a better antitumor drug than Tα1.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; B7-2 Antigen; Cell Line, Tumor; Cell Proliferation; Circular Dichroism; Female; Humans; Immune Tolerance; Lung Neoplasms; Lymphocyte Activation; Melanoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Nude; Oligopeptides; Protein Structure, Secondary; Recombinant Fusion Proteins; T-Lymphocytes; Thymalfasin; Thymosin; Trifluoroethanol; Xenograft Model Antitumor Assays

Recent understanding of the complex pathophysiology of melanoma and severe sepsis suggests that immune-modulating compounds such as thymosin alpha 1 (INN: thymalfasin; abbreviated Ta1) could be useful in the treatment of these two unrelated immune-suppressing indications.. Three nonclinical murine models were utilized, including: i) a lung metastasis B16 model; ii) a B16-based tumor growth model; and iii) a cecal-ligation and puncture (CLP) sepsis model.. In the lung metastasis model, Ta1 treatment alone led to a 32% decrease in metastases (p < 0.05). Additionally, combinations of Ta1 and an anti-PD-1 antibody led to significantly fewer metastases than vehicle. In the tumor growth model, significant decreases in tumor growth were seen: 34% (p = 0.015) to 46% (p = 0.001) depending on the Ta1 dose. In the CLP sepsis model, Ta1 treatment showed a positive trend towards increased survival and decreased bacterial load. In this CLP model, Ta1 also appeared to have an effect on the levels of some biomarkers.. All three models demonstrated a benefit after treatment with Ta1, with no evidence of toxicity. These initial pilot studies support the hypothesis that immune-suppressive indications, including sepsis and melanoma, may be treated with Ta1 alone or by Ta1 in combination with other immunotherapies.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Immunosuppressive Agents; Lung Neoplasms; Melanoma, Experimental; Mice; Sepsis; Skin Neoplasms; Thymalfasin; Thymosin

Thymosin alpha1 (Talpha1) is a 28 amino acid biologically active protein cleaved from positions 2-29 of a precursor protein, prothymosin alpha. Since its discovery, Talpha1 has been administered to animals and humans in a wide variety of settings and its pharmacologic effects are to enhance cellular immunity. Talpha1 administration is highly effective in settings where irradiation, chemotherapy, tumor burden, or immune senescence have caused a reduction of T cell number and/or function. Recent in vitro studies, including the one reported here, suggest that Talpha1 may act via pathways commonly used by various cytokines. This raises the possibility that Talpha1 and cytokines may have synergistic activity through potentiation of cytokine activity by Talpha1. Improved control of tumor growth when tumor-bearing mice were treated with Talpha1 and high doses of IL-2 has been previously reported. We extended those studies with the Lewis lung carcinoma mouse model using IRX-2, a natural well-defined biologic containing multiple cytokines, in combination with Talpha1 (IRX-3). Although IRX-2 was effective alone (using doses that contain significantly less IL-2 than in most typical studies), adding Talpha1 led to significant improvement in survival of the tumor-bearing mice. Based on these observations, the immunopharmacology of Talpha1 predicts an important clinical role for Talpha1 in the restoration of cellular immune activity when used in combination with cytokines. Patients who experience immune suppression due to the presence of tumor, irradiation, and/or chemotherapy or aging of the host would most benefit from this treatment combination.

Topics: Animals; Cytokines; Drug Synergism; Humans; Immunity, Cellular; Lung Neoplasms; Mice; Neoplasms, Experimental; Protein Kinase C; Thymalfasin; Thymosin

The ability of thymosin alpha1 (Talpha1) to prevent lung and breast cancer was investigated. Lung adenomas developed in A/J mice injected with carcinogens, such as urethane. The lung adenoma number was reduced by 15-45% if animals were daily treated subcutaneously (s.c.) with Talpha1 (0.4 mg/kg). Talpha1 (1 microM) directly inhibited the growth of mouse lung cell lines. These results suggest that Talpha1 may prevent mouse lung carcinogenesis because it directly inhibits the growth of lung cancer cells. Talpha1 prevented mammary carcinogenesis in two animal models. In the Fisher rat, an animal model of mammary cancer that is estrogen receptor dependent, tumors were initiated by the injection of N-methylurea (NMU). The rat survival was significantly increased by the daily injection of Talpha1. In the SV40T antigen mouse, a transgenic female mouse that spontaneously gets mammary cancer in an estrogen receptor-independent manner, survival was increased and tumor burden was significantly decreased by daily injection of Talpha1. These results indicate that Talpha1 is a chemopreventive agent in animal models for lung and breast carcinogenesis.

Topics: Adenoma; Animals; Anticarcinogenic Agents; Female; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Mice, Inbred A; Rats; Rats, Inbred F344; Thymalfasin; Thymosin

Clinical trails showed that thymosin alpha1 offers protection from toxicities (nausea, vomiting, fatigue) of chemotherapy. This study was designed to investigate the protection of thymosin alpha1 to nervous system.. Twenty-two patients with advanced lung cancer, or advanced breast cancer were treated with vinorelbine (25 mg/m(2), d(1), d(8)) combined with cisplatin (80 mg/m(2), d(1)), or gemcitabine (1.25 g/m(2), d(1), d(8)) combined with cisplatin (80 mg/m(2), d(1)),or paclitaxel (80 mg/m(2), d(1), d(8), d(15)) combined with carboplatin (AUC=6 d(1)),or paclitaxel (80 mg/m(2), d(1), d(8), d(15)) combined with epirubicin (80 mg/m(2), d(1)). They all experienced grade 2 to 4 of neurotoxicities according to common toxicity criteria of National Cancer Institute after chemotherapy. The same chemotherapy regimens were combined with thymosin alpha1 (1.6 mg/d for 4 days before chemotherapy, and 1.6 mg twice weekly for 1-3 weeks after chemotherapy began) in the next cycle. Clinical neurologic evaluation was performed at baseline every week.. In 10 patients (45.4%), neurotoxicities reduced from grade 2-4 before chemotherapy to less than grade 2 after chemotherapy.. Thymosin alpha1 may prevent patients from chemotherapy-induced neurotoxicities.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Constipation; Female; Humans; Hypesthesia; Hypokinesia; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Neuroprotective Agents; Thymalfasin; Thymosin

The effects of thymosin (THN) alpha1 were investigated using the urethane injection carcinogenesis A/J mouse model. Lung adenomas were observed 2.5, 3, and 4 months after urethane injection (400 mg/kg i.p.) into female A/J mice. Daily administration of THNalpha1 (0.4 mg/kg, s.c.) reduced lung adenoma multiplicity significantly, by approximately 45, 40, and 17%, respectively, 2.5, 3, and 4 months after urethane injection. Animals treated with THNalpha1 had a significantly greater white cell density than control A/J mice. Endogenous THNalpha1-like peptides were detected in the mouse lung. By radioimmunoassay and by Western blot, prothymosin alpha was detected in the mouse lung. By immunocytochemistry, THNalpha1-like peptides were detected in all lung compartments including the bronchus, adenoma, bronchioles, and alveoli. These results indicate that exogenous THNalpha1 prevents lung carcinogenesis in A/J mice.

Topics: Adenoma; Animals; Blood; Blotting, Western; Bronchi; Carcinogens; Female; Immunohistochemistry; Lung; Lung Neoplasms; Mice; Pulmonary Alveoli; Radioimmunoassay; Thymalfasin; Thymosin; Time Factors; Tissue Distribution; Urethane

The immunomodulatory and antimetastatic/antitumor activity of thymosin alpha(1) (Talpha(1)) was evaluated in BALB/c-mice. Daily subcutaneous application (7 consecutive days, 0.01-10 microg of Talpha(1)/injection per mouse) upregulated the number of thymocytes and peripheral blood cells in tumor bearing mice. To check the influence of Talpha(1) treatment on growth of experimental metastases, RAW H10 lymphosarcoma cells or L-1 sarcoma cells were intravenously injected into BALB/c-mice to establish liver or lung metastases. Local tumor growth was induced by subcutaneous injection of L-1 sarcoma cells. Talpha(1) was subcutaneously administered daily for 7 consecutive days starting 24 h after tumor cell challenge. Organ colonization, as well as local tumor growth, were investigated on day 14 after tumor cell inoculation, and demonstrated a statistically significant (P<0.05) reduction of experimental liver and lung metastases and local tumor growth for Talpha(1) treated mice.

Topics: Adjuvants, Immunologic; Animals; Cell Count; Dose-Response Relationship, Drug; Immunity; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Organ Size; Thymalfasin; Thymosin; Thymus Gland; Tumor Cells, Cultured

Prothymosin-alpha, the precursor of thymosin-alpha1, may play a role in cell proliferation, and the plasma level of thymosin-alpha1 may reflect the degree of proliferation of the tumor cells.. Recently, a new sandwich immunoradiometric assay for thymosin-alpha1 was developed using monoclonal and polyclonal antibodies. In this investigation, we used this assay to measure plasma and tissue level of thymosin-alpha1 in 131 lung cancer patients.. We found that the mean plasma thymosin-alpha1 levels in lung cancer patients were higher than in normal individuals (P < 0.001). However, half of the patients showed normal levels. Thymosin-alpha1 levels correlated neither with the stage nor pathological subtype of the lung cancer, and did not decrease significantly in the 4 weeks after the resection of the tumor. Thymosin-alpha1 levels of lung cancer patients with another cancer were higher than those without evidence of other cancers (P = 0.03). Survival of patients with normal levels of plasma thymosin-alpha1 was significantly better than that with higher levels (P = 0.04).. The plasma level of thymosin-alpha1 may be used as a marker for the prognosis of lung cancer patients. Further investigations are warranted to determine its role in the lung cancer.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Division; Female; Humans; Immunoradiometric Assay; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Thymalfasin; Thymosin

Topics: Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Line; Humans; Immune Sera; Lung Neoplasms; Radioimmunoassay; Sensitivity and Specificity; Thymalfasin; Thymosin; Tumor Cells, Cultured

The effect of thymosin alpha 1 (THN alpha 1) and its NH2-terminal fragment (THN1-14) and COOH-terminal fragment (THN15-28) on non-small cell lung cancer (NSCLC) growth was evaluated. Using an anti-THN alpha 1 antibody, receptors were identified on NSCLC cells that were pretreated with 10(-6) M THN alpha 1. [3H]Arachidonic acid was readily taken up by NSCLC cells and THN alpha 1 significantly increased the rate of arachidonic acid release. THN1-15 slightly stimulated but THN15-28 and THN beta 4 did not alter arachidonic acid release from NCI-H1299 cells. In clonogenic growth assays in vitro, THN alpha 1 (10(-6) M) significantly decreased NSCLC colony number whereas THN1-14, THN15-28, and THN beta 4 were less potent. Using growth assays in vivo, THN alpha 1 (10 micrograms s.c./day) but not THN1-14, THN15-28, or THN beta 4 inhibited significantly NSCLC xenograft formation in nude mice. These data suggest that biologically active THN alpha 1 receptors are present on NSCLC cells and that native THN alpha 1 inhibits the growth of human NSCLC.

Topics: Animals; Arachidonic Acid; Carcinoma, Non-Small-Cell Lung; Cell Division; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Kinetics; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Peptide Fragments; Thymalfasin; Thymosin; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Stem Cell Assay

A combination treatment with thymosin alpha 1 (200 micrograms/kg) for 4 days, followed by a single injection of murine interferon alpha/beta (3 x 10(4) international units/mouse). starting 2 days after cyclophosphamide treatment (200 mg/kg, single injection) demonstrated a dramatic and rapid disappearance of tumor burden in mice bearing Lewis lung carcinoma (3LL) tumor. The effectiveness of this new chemoimmunotherapy protocol was evident even on the long-term survival in a high percentage of animals, and was statistically significant when compared to treatment with the single agents in conjunction with chemotherapy or to chemotherapy itself. The same combination immunotherapy treatment strongly stimulated natural killer activity and cytotoxicity against autologus 3LL tumor cells in 3LL-tumor-bearing mice treated with cyclophosphamide, whereas treatments with each agent singly did not alter or only slightly modified the cytotoxic activity towards Yac-1 or 3LL target cells. Selective depletion with antibodies showed that killer cells stimulated by combination chemoimmunotherapy treatment bear phenotypic characteristics of asialo-GM1-positive cells. A histological study has shown a high number of infiltrating lymphoid cells in the tumors obtained from mice treated with combination chemoimmunotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Cyclophosphamide; Cytotoxicity, Immunologic; Immunotherapy; Interferon Type I; Interferon-gamma; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Phenotype; Thymalfasin; Thymosin

The effect of thymosin alpha 1 was examined in mice immunosuppressed by cytostatics or X-ray irradiation. Inoculation of B16 melanoma or L1210 leukemic cells into these immunosuppressed mice caused a high incidence of pulmonary metastasis or rapid death, respectively. Thymosin alpha 1 given concomitantly with cytostatics or after X-ray prevented such deleterious effects of these agents. One of possible mechanisms causing the rapid death and increasing the metastasis is the damage to NK cells. Thymosin alpha 1 prevented the reduction of NK cell activity caused by these agents. The preventive activity could be transferred to immunosuppressed recipients by spleen cells and those deprived of T cells, but not by those deprived of NK cells. Another possible mechanism is the aberration of the barrier system for spread of tumor cells in blood circulation, which may allow the tumor cells to migrate to various sites in the host. In 5-FU-treated mice, distribution of 125I-L1210 cells upon inoculation was higher in blood and lung, but lower in liver and spleen as compared with that in normal mice. On the other hand, when thymosin alpha 1 was given with 5-FU, the pattern of the tissue distribution was almost the same as that in normal mice. Thus, thymosin alpha 1 protected mice which received immunosuppressive agents from undesirable effects of the agents on surveillance systems against tumor. Thymosin alpha 1 may be useful as an adjuvant in cancer therapies.

Topics: Animals; Cell Survival; Immunosuppression Therapy; Immunosuppressive Agents; Killer Cells, Natural; Leukemia L1210; Lung Neoplasms; Mice; Neoplasms, Experimental; Thymalfasin; Thymosin