thymosin and Skin-Neoplasms

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

DTIC and interleukin-2 (IL-2), as single agents, have a limited anti-tumor activity in patients with metastatic melanoma. Experimentally, thymosin alpha 1 (TA1) may modulate the action of IL-2. We investigated the clinical and immunological effects of a combination with these three agents.. Forty-six patients with measurable metastatic melanoma were treated with DTIC 850 mg IV on day 1, TA1 2 mg s.c. on days 4 to 7, and IL-2 18 MU/m2/d by continuous intravenous infusion on days 8 to 12. Cycles were repeated every 3 weeks.. Objective responses were obtained in 15 (36%) of 42 evaluable patients (CI at 95%: 22%-50%). Two patients experienced complete responses, and stable disease was observed in five. The median time to progression was 5.5 months and median survival was 11 months. Side effects were predominantly caused by IL-2. Treatment was tolerated reasonably well, and there was no overlapping toxicity or interference between chemotherapy and biotherapy. Baseline sCD4 levels seem to correlate to tumor burden. Patients benefiting from treatment had lower sCD4 and higher sCD8 than did progressing patients.. The combination of DTIC + TA1 + IL-2 is active in the treatment of advanced melanoma, with acceptable toxicity. However, even more active regimens are needed, and the interactions between thymic hormones and cytokines should be further explored.

Topics: Adult; Aged; CD4 Antigens; CD8 Antigens; Combined Modality Therapy; Dacarbazine; Female; Humans; Interleukin-2; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Remission Induction; Skin Neoplasms; Thymalfasin; Thymosin

Di-(2-ethylhexyl) phthalate (DEHP) that is one of the most commonly used phthalates in manufacturing plastic wares regulates tumorigenesis. Thymosin beta-4 (TB4), an actin-sequestering protein, has been reported as a novel regulator to form primary cilia that are antenna-like organelles playing a role in various physiological homeostasis and pathological development including tumorigenesis. Here, we investigated whether DEHP affects tumor growth via primary cilium (PC) formation via the axis of TB4 gene expression and the production of reactive oxygen species (ROS). Tumor growth was increased by DEHP treatment that enhanced TB4 expression, PC formation and ROS production. The number of cells with primary cilia was enhanced time-dependently higher in HeLa cells incubated in the culture medium with 0.1% fetal bovine serum (FBS). The number of cells with primary cilia was decreased by the inhibition of TB4 expression. The incubation of cells with 0.1% FBS enhanced ROS production and the transcriptional activity of TB4 that was reduced by ciliobrevin A (CilioA), the inhibitor of ciliogenesis. ROS production was decreased by catalase treatment but not by mito-TEMPO, which affected to PC formation with the same trend. H

Topics: Animals; Carcinogenesis; Cell Survival; Cilia; Diethylhexyl Phthalate; HEK293 Cells; HeLa Cells; Humans; Hydrogen Peroxide; Injections, Intraperitoneal; Male; Melanoma, Experimental; Mice; Plasticizers; Skin Neoplasms; Thymosin

Numerous studies have revealed a variety of pathways involved in the development of melanoma, however, the molecular and genetic divergence of underlying mechanisms remain vague. In a mouse model, we studied the expression pattern of insulin-like growth factor 2 mRNA-binding protein 1 (Igf2bp1) and target genes microphthalmia-associated transcription factor (Mitf), v-myc avian myelocytomatosis viral oncogene homolog (Myc), B-cell lymphoma 2 (Bcl2), prothymosin alpha (Ptma) and melan-A (Mlana) in relation to tumor-growth characteristics. The in vivo expression of the aforementioned genes was assessed by quantitative Real Time-Polymerase Chain Reaction (RT-PCR) in tumors established by B16-F1-derived clones. Gene expression was correlated with tumor growth characteristics. Simultaneous expression of elevated levels of Myc, Igf2bp1, Ptma and Mitf characterizes tumors with a more aggressive phenotype. Our findings introduce a tumor-specific molecular signature possibly associated with melanoma heterogeneity. The concomitant overexpression of key molecules such as IGF2BP1, PTMA, MYC and MITF could serve as prognostic or predictive marker.

Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genotype; Melanoma, Experimental; Mice, Inbred C57BL; Microphthalmia-Associated Transcription Factor; Phenotype; Protein Precursors; Proto-Oncogene Proteins c-myc; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins; Skin Neoplasms; Thymosin; Time Factors; Tumor Burden

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

In the present study, the immunomodulatory and synergistic anti-tumor activity of thymosin α1-thymopentin fusion peptide (Tα1-TP5) was investigated in vivo. In addition, the potential receptor of Tα1-TP5 was investigated by surface plasmon resonance (SPR) binding studies. It was found that Tα1-TP5 (305 μg/kg) alleviated immunosuppression induced by hydrocortisone (HC). Tα1-TP5 (305 μg/kg) combined with cyclophosphamide (CY) had a better tumor growth inhibitory effect than CY alone. Furthermore, Tα1-TP5 had a higher affinity (KD=6.84 μmol/L) to toll-like receptor 2 (TLR2) than Tα1 (K(D)=35.4 μmol/L), but its affinity was not significantly different from that of TP5. The results of our present work indicate that Tα1-TP5 can possibly be developed as a new immunomodulatory agent.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Atrophy; B7-2 Antigen; Cyclophosphamide; Drug Synergism; Histocompatibility Antigens Class I; Hydrocortisone; Immunologic Factors; Immunosuppressive Agents; Interferon-gamma; Male; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protein Binding; Skin Neoplasms; Surface Plasmon Resonance; Thymalfasin; Thymocytes; Thymopentin; Thymosin; Thymus Gland; Time Factors; Toll-Like Receptor 2; Tumor Burden

This study generated a transgenic zebrafish line Tg(k18:Ptmaa-RFP) with overexpression of Prothymosin alpha type a (Ptmaa) in the skin epidermis. Red fluorescence first appears very weakly in the early stage, become stronger and mainly restricted in the nuclei of the epithelial cells from 3 dpf-larvae to adult fish. However, no evident morphological abnormalities were observed. Thus, overexpression of Ptmaa alone is not sufficient to cause disorganized growths or even cancer in zebrafish skin. Molecular and histological evidences showed that Tg(k18:Ptmaa-RFP) embryos have more proliferating cells in the pelvic fins [WT: 3.92 +/- 7.15; Tg(k18:Ptmaa-RFP): 38.00 +/- 10.87] and thicker skin [WT: 10.98 +/- 1.41 mum; Tg(k18:Ptmaa-RFP): 14.02 +/- 1.32 mum], indicating that overexpression of Ptmaa can promote proliferation. On the other hand, fewer apoptotic signals were found when Tg(k18:Ptmaa-RFP) embryos were exposed to UVB. Together with quantitative RT-PCR data, we suggest that UVB-induced epidermal cell apoptosis of zebrafish larvae can be attenuated by overexpression of Ptmaa through the enhancement of transcriptions of bcl2 mRNAs. Taken together, we conclude that overexpression of Ptmaa in zebrafish epidermal cells promotes proliferation and attenuates UVB-induced apoptosis but does not cause skin cancer.

Topics: Animals; Animals, Genetically Modified; Apoptosis; Carcinoma; Cell Proliferation; Embryo, Nonmammalian; Epidermis; Gene Expression; Gene Transfer Techniques; Protein Precursors; Skin Neoplasms; Thymosin; Ultraviolet Rays; Up-Regulation; Zebrafish

S-adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the synthesis of polyamines essential for cell growth and proliferation. Its overexpression induces the transformation of murine fibroblasts in both sense and antisense orientations, yielding highly invasive tumors in nude mice. These cell lines hence provide a good model to study cell invasion. Here, the gene expression profiles of these cells were compared with their normal counterpart by microarray analyses (Incyte Genomics, Palo Alto, CA, and Affymetrix, Santa Clara, CA). Up-regulation of the actin sequestering molecule thymosin beta4 was the most prominent change in both cell lines. Tetracycline-inducible expression of thymosin beta4 antisense RNA caused a partial reversal of the transformed phenotype. Further, reversal of transformation by dominant-negative mutant of c-Jun (TAM67) caused reduction in thymosin beta4 mRNA. Interestingly, a sponge toxin, latrunculin A, which inhibits the binding of thymosin beta4 to actin, was found to profoundly affect the morphology and proliferation of the AdoMetDC transformants and to block their invasion in three-dimensional Matrigel. Thus, thymosin beta4 is a determinant of AdoMetDC-induced transformed phenotype and invasiveness. Up-regulation of thymosin beta4 was also found in ras-transformed fibroblasts and metastatic human melanoma cells. These data encourage testing latrunculin A-like and other agents interfering with thymosin beta4 for treatment of thymosin beta4-overexpressing tumors with high invasive and metastatic potential.

Topics: Adenosylmethionine Decarboxylase; Animals; Cell Transformation, Neoplastic; Fibroblasts; Gene Expression Profiling; Humans; Melanoma; Mice; Neoplasm Invasiveness; Oligonucleotide Array Sequence Analysis; Phenotype; Skin Neoplasms; Thymosin; Up-Regulation

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

When screening a subtraction library for sequences that were specifically expressed in highly metastatic human melanoma cell lines, a cDNA clone was isolated encoding thymosin beta-10. We found that expression of thymosin beta-10 mRNA was associated with metastatic behavior of various human melanoma cell lines in nude mice. Furthermore, Northern blot analysis showed that also in freshly harvested human melanocytic lesions thymosin beta-10 was differentially expressed. Although expression of thymosin beta-10 was also examined in other non-melanoma model systems and materials, no clear relation could be established with metastatic potential or malignancy. Therefore, we conclude that thymosin beta-10 can be considered as a new progression marker for human cutaneous melanoma.

Topics: Amino Acid Sequence; Animals; Base Sequence; Biomarkers, Tumor; Female; Gene Expression; Humans; Male; Melanoma; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Proteins; Neoplasm Transplantation; Organ Specificity; Rats; Skin Neoplasms; Thymosin; Tumor Cells, Cultured

One hundred and fifty-six patients were screened for the presence of urinary melanoma antigen and serum cytoplasmic antibody. It was found that 44% of symptomless Stage 1 patients tested five to 15 years after operation had detectable antigen (Ag) in their urine; the urines of 67% of Stage 2A (local recurrence) patients were positive for Ag; while in only 38% of those patients graded 2B (lymph-node involvement) were these tests positive. Urines of 83% of patients with generalized metastases (Stage 3) were positive. A sequential study was made of 23 patients seen and treated in 1976. Of this group, 14 reverted from a positive state to a negative one following excision of their tumour, while six were negative on first postoperative testing and subsequently became positive. Three out of the 23 remained persistently negative. T lymphocyte levels were assessed in 71 melanoma patients, and a stage-related fall was noticed. Thymosin (Hoffman LaRoche) on in vitro incubation significantly raised the levels of T lymphocytes.

Topics: Adult; Aged; Antigens, Neoplasm; Child, Preschool; Female; Humans; In Vitro Techniques; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms; Stimulation, Chemical; T-Lymphocytes; Thymosin; Thymus Hormones

E rosette-forming (T) lymphocytes and surface immunoglobulin-bearing lymphocytes were estimated in 85 patients with malignant melanoma. The melanoma patient group had lower mean levels of T lymphocytes and higher mean levels of immunoglobulin-bearing (? B) lymphocytes than did normal subjects. The absolute and percentage depressions of T-cell levels in the melanoma patients were stage-related, as was the depression of total lymphocyte and B-lymphocyte levels. The T lymphopenia in the melanoma patients could, in vitro, be partially abolished by fetal calf serum (as used in many E rosetting methods), and could be totally abolished by thymosin fraction 5 (Hoffmann-La Roche) at optimum concentration. In view of the ability of thymosin to restore T cells to normal levels in all of the T-lymphopenic patients, a clinical trial of this hormone in selected melanoma patients of all stages appears to be warranted.

Topics: Adolescent; Adult; Aged; Female; Humans; In Vitro Techniques; Lymphopenia; Male; Melanoma; Middle Aged; Rosette Formation; Skin Neoplasms; T-Lymphocytes; Thymosin; Thymus Hormones