thymosin and Carcinoma--Non-Small-Cell-Lung

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

In a major study that showed a treatment advantage for induction chemotherapy followed by radiation therapy (CALGB 8433), there was a significantly (P = 0.02) lower proportion of patients dying within 105 days of registration in the chemotherapy/radiation arm than the radiation therapy arm; without this difference, the overall survival was marginally better (P = 0.059) for the chemotherapy/radiation group. A retrospective analysis of RTOG trials sought explanations for the phenomenon.. Patients who fit the CALGB eligibility criteria and received radiation therapy alone in four prospective trials of the RTOG conducted between 1983 and 1989 were analyzed to determine factors that distinguished patients dying within 105 days from longer survivors. Two were trials of altered fractionation and two used standard fractionation. Of 683 patients identified, 107 (15.7%) died within 105 days after registration. The log linear model was used to evaluate relationships between death within 105 days and known prognostic factors. Karnofsky performance status (KPS), < 90 vs. > or = 90, was the only factor significantly related to death within 105 days (P = 0.0052). A Cox model with the same factors plus fractionation and total dose found KPS and T-stage associated with overall survival (P = 0.0005 and 0.025, respectively). The choice of the hyperfractionation arm (HFX) for Phase III study (69.6 Gy at 1.2 Gy b.i.d.) was based in part on comparison with standard fractionation (STD) from a concurrent RTOG protocol, 8321. Review of early deaths showed that this HFX arm had a lower proportion of patients dying within 105 days (7.9%) than STD in 8321 (21.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Combined Modality Therapy; Cranial Irradiation; Female; Humans; Linear Models; Lung Neoplasms; Male; Middle Aged; Models, Theoretical; Prognosis; Proportional Hazards Models; Radiotherapy Dosage; Remission Induction; Retrospective Studies; Survival Analysis; Survival Rate; Thymosin; Treatment Outcome

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

The present study aimed to explore the role of the long noncoding RNA cytoskeleton regulator (CYTOR) in non‑small cell lung cancer (NSCLC) radiosensitivity by manipulating the microRNA (miR)‑206/prothymosin α (PTMA) axis. First, 58 pairs of NSCLC and paracancerous tissues, normal human lung epithelial cells and NSCLC cells were collected to analyze CYTOR expression and the relationship between CYTOR and NSCLC prognosis. Subsequently, CYTOR expression in radioresistant cells was assessed. Radioresistant cells with low CYTOR expression and parental cells with high CYTOR expression were established. Functional assays were then performed to assess changes in cell radiosensitivity after irradiation treatment. Subsequently, the downstream mechanism of CYTOR was explored. The binding interactions between CYTOR and miR‑206 and between miR‑206 and PTMA were predicted and certified. Xenograft transplantation was applied to confirm the role of CYTOR in the radiosensitivity of NSCLC. CYTOR was overexpressed in NSCLC and was associated with poor prognosis. CYTOR was further upregulated in NSCLC cells with radioresistance. CYTOR knockdown enhanced the radiosensitivity of NSCLC cells, while overexpression of CYTOR led to the opposite result. Mechanistically, CYTOR specifically bound to miR‑206 and silencing CYTOR promoted miR‑206 to enhance the radiosensitivity of NSCLC cells. PTMA is a target of miR‑206 and silencing CYTOR inhibited PTMA expression via miR‑206, thus promoting radiosensitivity of NSCLC cells. CYTOR knockdown also enhanced NSCLC cell radiosensitivity

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cytoskeleton; Down-Regulation; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; MicroRNAs; Prognosis; Protein Precursors; Radiation Tolerance; RNA, Long Noncoding; Thymosin

Thymosin beta 4 (Tβ4), a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes, has been reported to be strongly associated with tumorigenesis. A recent tissue microarray analysis showed that Tβ4 was highly expressed in certain tumor cells, including lung cancer. However, the exact expression pattern and the role of Tβ4 in non-small cell lung cancer (NSCLC) have not to our knowledge been investigated. In the present study, we confirmed that Tβ4 expression was increased in NSCLC tissues and cell lines. Tβ4 gene silencing in A549 and H1299 cells inhibited cell proliferation, migration, and invasion in vitro and decreased tumor growth in vivo Mechanistic investigations revealed a significant decrease in Notch1 activation in Tβ4 gene-silenced cells. Moreover, restoring the Notch1 expression attenuated the function of Tβ4 silencing in NSCLC cells. Taken together, these findings suggest that Tβ4 may play an oncogenic role in NSCLC progression and may be a novel molecular target for anti-NSCLC therapy.

Topics: A549 Cells; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Silencing; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Invasiveness; Receptor, Notch1; Signal Transduction; Thymosin; Xenograft Model Antitumor Assays

Lung cancer is the leading cause of cancer-related deaths worldwide and is usually associated with a late diagnosis and a poor prognosis. Thymosin β(10) (TMSB10) is a monomeric actin sequestering protein that regulates actin cytoskeleton organization. The aberrant TMSB10 expression has been implicated in the pathogenesis of human cancers. However, its role in carcinogenesis is still controversial. To better understand the role of TMSB10 in lung tumorigenesis and its regulatory mechanism, we examined the methylation status and expression of the TMSB10 gene in non-small cell lung cancers (NSCLCs) using methylation-specific PCR (MSP) and immunohistochemistry (IHC), respectively. MSP analysis showed that the TMSB10 promoter was already unmethylated in most tumor tissues and became demethylated in 20 (14.4%) of the 139 NSCLCs. TMSB10 hypomethylation was not significantly correlated with the clinicopathological features. IHC showed that the TMSB10 protein was strongly expressed in the cytoplasm of malignant cells and its overexpression was detected in 50.0% of the tumor tissues compared to normal tissues. TMSB10 overexpression was frequently observed in sqaumous cell carcinomas compared to adenocarcinomas with border line significance (P = 0.072). However, TMSB10 methylation status was not linked to its overexpression. Collectively, these results suggest that TMSB10 hypomethylation may be a frequent event in NSCLCs, but it may not be a common mechanism underlying TMSB10 overexpression. However, further studies with large numbers of patients are needed to confirm our findings.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Transformation, Neoplastic; Disease Progression; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Neoplasm Staging; Promoter Regions, Genetic; Survival Analysis; Thymosin; Up-Regulation

The exact role of thymosin beta10 in lung cancer progression remains unclear. We investigated by immunohistochemistry the expression of thymosin beta10 protein in tumors and tumor-adjacent tissues from 69 patients with non-small cell lung cancer. The relationship of thymosin beta10 expression with vascular endothelial growth factor, vascular endothelial growth factor-C, microvessel density, and lymphatic vessel density was determined; clinicopathologic factors and surgical treatment outcome were also studied. The results showed that thymosin beta10 was mainly expressed in the cytoplasm of lung cancer cells, and the overexpression of thymosin beta10 was correlated with advanced clinical stage (P = .026), distant metastases (P = .016), lymph node metastases (P = .007), poor degree of differentiation (P = .03), and poor postoperative survival (P = .004). Furthermore, thymosin beta10 overexpression was associated with vascular endothelial growth factor (P = .004), vascular endothelial growth factor-C (P = .017), microvessel density (P = .000), and lymphatic vessel density (P = .002). The lowest survival rate was observed in the patients with high thymosin beta10, positive vascular endothelial growth factor, and high microvessel density (P = .007) or in the patients with high thymosin beta10, positive vascular endothelial growth factor-C, and high lymphatic vessel density (P = .005). These results suggest that thymosin beta10 might induce microvascular and lymphatic vessel formation by up-regulating vascular endothelial growth factor and vascular endothelial growth factor-C in lung cancer tissues, thus promoting the distant and lymph node metastases and being implicated in the progression of non-small cell lung cancer.

Topics: Carcinoma, Non-Small-Cell Lung; Female; Humans; Immunohistochemistry; Lung Neoplasms; Lymphatic Metastasis; Lymphatic Vessels; Male; Microvessels; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Analysis; Thymosin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C

Thymosin beta15 (Tbeta15) is a small protein that comprises 44 amino acid residues. Tbeta15 is upregulated in malignant human prostate and breast tumors. The expression of Tbeta15 correlates with the metastatic potential of mouse lung cancer and human breast carcinoma cells. However, the correlation of Tbeta15 expression with human lung cancer remains unclear. Using immunohistochemistry and in situ hybridization, we analyzed the expression of Tbeta15 in tumors and tumor-adjacent tissues obtained from 76 patients with non-small cell lung cancer (NSCLC). The relationship between Tbeta15 expression and clinicopathological factors was investigated. Our findings showed that in NSCLC, Tbeta15 protein and mRNA were mainly expressed in the cytoplasm, and their expression correlated with stage (p=0.018 for both), differentiation (p=0.013 and 0.006, respectively), and lymph node metastasis (p=0.001 and 0.009, respectively). Tbeta15 expression was examined in PG-BE1 and PG-LH7 lung cancer cells. We found that both Tbeta15 protein and mRNA were highly expressed in BE1 cells as compared to LH7 cells. After transfecting the PG-LH7 cells with the pEGFP-Tbeta15 plasmid in order to increase Tbeta15 expression, the migration ability of the cells was enhanced. These findings suggest that increased Tbeta15 expression correlates with the progression and metastasis of NSCLC.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Disease Progression; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; RNA, Messenger; Thymosin; Transfection; Up-Regulation

Early-stage non-small cell lung cancer (NSCLC) can be cured by surgical resection, but a substantial fraction of patients ultimately dies due to distant metastasis. In this study, we used subtractive hybridization to identify gene expression differences in stage I NSCLC tumors that either did or did not metastasize in the course of disease. Individual clones (n=225) were sequenced and quantitative RT-PCR verified overexpression in metastasizing samples. Several of the identified genes (eIF4A1, thymosin beta4 and a novel transcript named MALAT-1) were demonstrated to be significantly associated with metastasis in NSCLC patients (n=70). The genes' association with metastasis was stage- and histology specific. The Kaplan-Meier analyses identified MALAT-1 and thymosin beta4 as prognostic parameters for patient survival in stage I NSCLC. The novel MALAT-1 transcript is a noncoding RNA of more than 8000 nt expressed from chromosome 11q13. It is highly expressed in lung, pancreas and other healthy organs as well as in NSCLC. MALAT-1 expressed sequences are conserved across several species indicating its potentially important function. Taken together, these data contribute to the identification of early-stage NSCLC patients that are at high risk to develop metastasis. The identification of MALAT-1 emphasizes the potential role of noncoding RNAs in human cancer.

Topics: Carcinoma, Non-Small-Cell Lung; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Lung Neoplasms; Molecular Sequence Data; Neoplasm Metastasis; Neoplasm Staging; Predictive Value of Tests; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Untranslated; Survival Rate; 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