thymosin and Melanoma

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

Thymosin α1 (Tα1) is an immunomodulatory peptide released by the thymus gland in mammals. It was first described in 1977 as a potential agent for the treatment of immune deficiencies and cancer. Among solid tumors, a number of clinical trials have investigated the activity of Tα1 in melanoma. In particular, a large randomized phase II trial that evaluated the safety and efficacy of combining Tα1 with dacarbazine and interferon alpha in metastatic melanoma patients provided the rationale for further clinical applications. The main findings emerging from clinical trials and that support the therapeutic use of Tα1 in human melanoma are summarized and discussed.

Topics: Antineoplastic Agents, Alkylating; Clinical Trials, Phase II as Topic; Dacarbazine; Humans; Immunologic Factors; Immunotherapy; Melanoma; Randomized Controlled Trials as Topic; Thymosin

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 alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Talpha1 with dacarbazine (DTIC) and interferon alfa (IFN-alpha) in patients with metastatic melanoma.. Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-alpha+Talpha1 (1.6 mg); DTIC+IFN-alpha+Talpha1 (3.2 mg); DTIC+IFN-alpha+Talpha1 (6.4 mg); DTIC+Talpha1 (3.2 mg); DTIC+IFN-alpha (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months.. Ten and 12 tumor responses were observed in the DTIC+IFN-alpha+Talpha1 (3.2 mg) and DTIC+Talpha1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P(0) < or = .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Talpha1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Talpha1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Talpha1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Talpha1 to DTIC and IFN-alpha did not lead to any additional toxicity.. These results suggest Talpha1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Female; Humans; Interferon-alpha; Male; Melanoma; Middle Aged; Thymalfasin; Thymosin

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Combined Modality Therapy; Dacarbazine; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Humans; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Killer Cells, Natural; Lymphopenia; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Safety; Survival Analysis; Thymalfasin; Thymosin; Treatment Outcome

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

Studies in a variety of animal and human models indicate that thymosin plays a role in the differentiation of a number of T-cell subpopulations. The hypothesis presented is that a normal immune balance depends heavily upon the presence of thymosin-activated suppressor or regulator T-cells. A major thrust in our present research program is to determine whether or not the various disorders discussed here are causally related to abnormal thymosin production by the thymus gland. We are also assessing in animal models the potential value of thymsin in the treatment of specific autoimmune diseases. This information may yield new insights for the management of autoimmune type disorders such as SLE. Results from clinical trials to date suggest that thymosin will have a role in boosting the immune responses of patients with specific thymic malfunctions and may indeed exert an influence via the production of suppressor or regulator T-cells.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Clinical Trials as Topic; Hodgkin Disease; Humans; Immune Adherence Reaction; Immunologic Deficiency Syndromes; Leiomyosarcoma; Leukemia, Lymphoid; Lung Neoplasms; Melanoma; Mice; Multiple Myeloma; T-Lymphocytes; Thymosin; Thymus Extracts

Thymosin β4 (Tβ4) is a small, 44-amino acid polypeptide. It has been implicated in multiple processes, including cell movement, angiogenesis, and stemness. Previously, we reported that melanoma cell lines differ in Tβ4 levels. Studies on stable clones with silenced

Topics: Actin Cytoskeleton; Biomarkers, Tumor; Biomechanical Phenomena; Carcinogenesis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Shape; Gene Silencing; Humans; Intermediate Filaments; Melanoma; Models, Biological; Neoplastic Stem Cells; Nestin; Thymosin; Vimentin

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

Thymosin α1 (Tα1), a hormone containing 28 amino acids, has been approved in several cancer therapies, but the lack of tumor-targeting hinders its full use in tumor treatment. We designed a new peptide by connecting Tα1 and RGDR, generating a product, Tα1-RGDR, where RGDR is located in the C-end with both tumor-homing and cell internalizing properties (C-end rule peptides, a consensus R/KXXR/K motif). This work aimed to study the antitumor and immunological activities of Tα1-RGDR, and its differences compared with the wild-type Tα1. The antitumor and immunological activities of Tα1-RGDR were measured using the B16F10 tumor and immunologic suppression models. Tα1-RGDR treatment led to significant inhibition of tumor growth at a dose at which Tα1 showed a slight effect in the B16F10 tumor growth model. In the immunologic suppression model, Tα1-RGDR shared almost equivalent immunomodulatory effect with Tα1. These results demonstrated the better therapeutic effects after treatment with Tα1-RGDR compared with Tα1. Moreover, both Tα1-RGDR and Tα1 shared a helical conformation in the presence of trifluoroethanol based on CD spectroscopy. Our dock information of Tα1-RGDR when combined with integrin αvβ3 or neuropilin-1 further confirmed previous experimental results. All these findings suggest that Tα1-RGDR might be a useful therapy for tumors by overcoming its wild type limitation of tumor homing.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Melanoma; Mice; Thymalfasin; Thymosin

Melanoma is a malignancy characterized by high invasive/metastatic potential, with no efficient therapy after metastasis. Understanding the molecular mechanisms underlying the invasive/metastatic tendency is therefore important. Our genome-wide gene expression analyses revealed that human melanoma cell lines WM793 and especially WM239 (vertical growth phase and metastatic cells, respectively) overexpress the extracellular matrix (ECM) protein transforming growth factor β induced (TGFBI). In adhesion assays, recombinant TGFBI was strongly anti-adhesive for both melanoma cells and skin fibroblasts. TGFBI further impaired the adhesion of melanoma cells to the adhesive ECM proteins fibronectin, collagen-I, and laminin, known to interact with it. Unexpectedly, WM239 cells migrated/invaded more effectively in three-dimensional collagen-I and Matrigel cultures after knockdown of TGFBI by shRNA expression. However, in the physiological subcutaneous microenvironment in nude mice, after TGFBI knockdown, these cells showed markedly impaired tumor growth and invasive capability; the initially formed small tumors later underwent myxoid degeneration and completely regressed. By contrast, the expanding control tumors showed intense TGFBI staining at the tumor edges, co-localizing with the fibrillar fibronectin/tenascin-C/periostin structures that characteristically surround melanoma cells at invasion fronts. Furthermore, TGFBI was found in similar fibrillar structures in clinical human melanoma metastases as well, co-localizing with fibronectin. These data imply an important role for TGFBI in the ECM deposition and invasive growth of melanoma cells, rendering TGFBI a potential target for therapeutic interventions.

Topics: Actin Cytoskeleton; Animals; Cell Adhesion; Cell Movement; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genome-Wide Association Study; Humans; Integrin beta1; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasm Transplantation; Recombinant Proteins; Skin; Talin; Thymosin; Transforming Growth Factor beta; Tumor Cells, Cultured; Up-Regulation

Thymosin beta4 (Tbeta4) is a major actin-sequestering protein that has been implicated in the growth, survival, motility, and metastasis of certain tumors and is considered an indicator for malignant progression. Therefore, identifying compounds that can downregulate Tbeta4 expression is very important for the development of anti-cancer chemotherapies. In this study, we investigated the effects of elevated cAMP on Tbeta4 expression and the metastatic potential of murine B16 melanoma cells. In addition, we also dissected the mechanism underlying cAMP-mediated Tbeta4 suppression. We found that treatment with the cAMP-inducing compounds alpha-MSH (alpha-melanocyte stimulating hormone) and IBMX (3-isobutyl-1-methylxanthine) significantly suppressed Tbeta4 expression and regulated EMT-associated genes through the suppression of NF-kappaB activation in B16F10 cells. Along with decreased Tbeta4 expression, the in vitro invasiveness and anchorage-independent growth in a semi-solid agar of these cells were also inhibited. In animal experiments, the metastatic potential of the alpha-MSH- or IBMX-treated B16F10 melanoma cells was decreased compared to untreated control cells. Collectively, our data demonstrate that elevated intracellular cAMP significantly suppresses Tbeta4 expression and reduces MMP-9 activity, which leads to decreased metastatic potential. Moreover, suppression of NF-kappaB activation by alpha-MSH or IBMX is critical for inhibiting Tbeta4 expression.

Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclic AMP; Gene Expression Regulation, Neoplastic; Matrix Metalloproteinase 9; Melanoma; Melanoma, Experimental; Mice; Neoplasm Metastasis; NF-kappa B; Thymosin

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

Topics: Animals; Fibronectins; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mice; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; ras Proteins; rho GTP-Binding Proteins; rhoC GTP-Binding Protein; Thymosin; Tumor Cells, Cultured; Up-Regulation

The most damaging change during cancer progression is the switch from a locally growing tumour to a metastatic killer. This switch is believed to involve numerous alterations that allow tumour cells to complete the complex series of events needed for metastasis. Relatively few genes have been implicated in these events. Here we use an in vivo selection scheme to select highly metastatic melanoma cells. By analysing these cells on DNA arrays, we define a pattern of gene expression that correlates with progression to a metastatic phenotype. In particular, we show enhanced expression of several genes involved in extracellular matrix assembly and of a second set of genes that regulate, either directly or indirectly, the actin-based cytoskeleton. One of these, the small GTPase RhoC, enhances metastasis when overexpressed, whereas a dominant-negative Rho inhibits metastasis. Analysis of the phenotype of cells expressing dominant-negative Rho or RhoC indicates that RhoC is important in tumour cell invasion. The genomic approach allows us to identify families of genes involved in a process, not just single genes, and can indicate which molecular and cellular events might be important in complex biological processes such as metastasis.

Topics: Animals; Fibronectins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; Humans; Lung Neoplasms; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; ras Proteins; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; rhoC GTP-Binding Protein; Thymosin; Tumor Cells, Cultured

Immunoregulatory effects of thymic peptides on functions of polymorphonuclear leukocytes (PMNs) are poorly investigated. We studied the effects of prothymosin alpha 1 (Pro alpha 1) on PMNs from patients with colorectal tumors, breast tumors and melanoma (total n = 37) in comparison with healthy donors (n = 18), with respect to chemotaxis, cytotoxicity against HCT-116 colon tumor cells, oxidative response (chemiluminescence reaction) as well as expression of surface marker molecules. We found that Pro alpha 1 was equally effective in stimulating the chemotactic activity of PMNs from tumor patients and healthy donors (43% increase). PMNs from tumor patients, especially with breast tumor, showed a significant enhancement of cytotoxicity against the tumor target cells in comparison with healthy donors. With respect to the PMNs cytotoxicity, only about 50% of the colorectal tumor patients and healthy donors responded to Pro alpha 1 and FMLP. As to the oxidative response of PMNs, elevated levels were found only among colorectal tumor patients. Pro alpha 1 significantly increased the oxidative response in breast and colorectal tumor patients by 55% and 25%, respectively. Pro alpha 1 decreased the expression of CD16 on PMNs of healthy donors, but not that of CD11a, CD11b, CD11c, CD13, CD14, CD15 and CD32. Therefore, we suggest, that Pro alpha 1 may improve some PMN functions of tumor patients, associated with the proposed role in host-tumor interaction.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Chemotaxis, Leukocyte; Cytotoxicity, Immunologic; Female; Humans; Luminescent Measurements; Macrophage-1 Antigen; Male; Melanoma; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Protein Precursors; Reactive Oxygen Species; Receptors, IgG; Thymosin

The effects of prothymosin alpha 1 (Pro alpha 1) on the natural killer (NK), lymphokine (IL-2)-activated killer (LAK) cell activity and the phytohaemagglutinin (PHA)-induced IL-2 secretion of peripheral blood T-lymphocytes (PBL) from 34 malignant melanoma patients of all clinical stages were studied in vitro. On average, melanoma patients showed lower NK and LAK cell activities than healthy donors. In particular, patients with metastases revealed an impaired NK cell activity. However, individuals showed a broad range of LAK cell sensitivity to Pro alpha 1 depending, among other factors, on the disease stage. LAK cell activities were not correlated to tumour stage. Patients' impaired LAK cell activity could be restored by Pro alpha 1. Only patients at stage II (regional metastases) responded to Pro alpha 1. The IL-2 secretion from PBL melanoma and healthy donors did not differ, Pro alpha 1 administration was without any significant effect. However, stage III (distant metastases) PBL expressed significantly lower IL-2 levels, compared to stage I (primary tumours). The highest IL-2 levels was found to be associated with tumour stage II. Pro alpha 1 enhanced the IL-2 secretion from stage I PBL. Therefore Pro alpha 1 administration abrogated the defective LAK cell activity and IL-2 secretion of PBL, mainly from patients at early melanoma stages.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Interleukin-2; Killer Cells, Lymphokine-Activated; Lymphocytes; Male; Melanoma; Middle Aged; Protein Precursors; Thymosin; Tumor Cells, Cultured

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

In this report we describe the characterization of the immunomodulatory efficiency and therapeutic properties of thymosin fraction five (F5). We consistently observed the immunostimulation of T-cell activity in assays of allogeneic mixed lymphocyte response (MLR) and the development of cytotoxic effector cells in an allogeneic mixed lymphocyte tumor response-cell-mediated cytotoxicity assay (MLTR-CMC). No induction of suppressor cell activity was observed. Thymosin F5 also acted successfully as an adjuvant when admixed with irradiated tumor cells. We were unable to demonstrate either NK cell or macrophage activation by thymosin F5. Therapeutic protocols using thymosin F5 and directed against pre-existing experimental and spontaneous metastases, had a significant immunotherapeutic potential.

Topics: Animals; Cell Line; Fibrosarcoma; Immunotherapy; Leukemia, Experimental; Lymphocyte Culture Test, Mixed; Male; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Radiation-Induced; T-Lymphocytes; Thymosin; Ultraviolet Rays

Thymosin, a product of the endocrine system, was used to further define the effects of immunomodulation of metastasis. Adult thymectomized C57BL/6 mice, 4 wk post-irradiation (400 R) had a decrease in the number of pulmonary metastasis (compared to controls) following tail vein injection of 5 X 10(4) B16 melanoma cells. Thymosin fraction 5 (fr. 5) administration (200 micrograms/mouse, 3 times weekly beginning 2 days post-thymectomy) returned the number of metastasis to the nonthymectomized values. Thymosin treatment of sham-operated, sham-operated irradiated, or thymectomized nonirradiated mice did not significantly elevate the number of metastases compared to the respective controls. Variant tumors which have an increase in metastasis following thymectomy and irradiation were also used. Thymosin administration reversed the effects of thymectomy in such variants, resulting in a decrease in metastasis. Metastases in thymosin-treated control mice were not significantly altered. A role for the thymus in metastasis via an endocrine product (thymosin) is suggested by these studies. Since thymosin did not increase metastasis in intact mice with tumors, further clinical trials with thymosin in cancer patients are not counterindicated by our results. These experiments confirm that thymosin fr. 5 is an important probe of the immunoendocrine events involved in tumor growth and metastasis.

Topics: Animals; Immunity; Melanoma; Mice; Neoplasm Metastasis; Thymectomy; Thymosin; Thymus Gland

Thymosin fraction 5, an immunopotentiating thymic preparation, significantly increases the cytotoxic capacity of NK cells isolated from the spleen. This stimulation is inhibited by testosterone and estradiol.

Topics: Animals; Cytotoxicity, Immunologic; Drug Antagonism; Estradiol; Female; Killer Cells, Natural; Male; Melanoma; Mice; Neoplasms, Experimental; Testosterone; 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

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

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