1. Interferon-gamma is induced in human peripheral blood immune cells in vitro by sodium stibogluconate/interleukin-2 and mediates its antitumor activity in vivo.
- Author
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Fan K, Borden E, and Yi T
- Subjects
- Animals, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte genetics, Antimony Sodium Gluconate administration & dosage, Antineoplastic Agents administration & dosage, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cells, Cultured, Dose-Response Relationship, Drug, Female, Growth Inhibitors administration & dosage, Humans, Immunophenotyping, Interferon-gamma genetics, Interferon-gamma immunology, Interleukin-2 immunology, Interleukin-5 genetics, Interleukin-5 immunology, Kidney Neoplasms pathology, Kidney Neoplasms therapy, Lectins, C-Type, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear pathology, Lymphocyte Activation drug effects, Male, Melanoma pathology, Melanoma therapy, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasm Transplantation, Protein Tyrosine Phosphatase, Non-Receptor Type 6 antagonists & inhibitors, Signal Transduction, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, Antimony Sodium Gluconate pharmacology, Antineoplastic Agents pharmacology, Growth Inhibitors pharmacology, Interferon-gamma metabolism, Interleukin-2 metabolism, Interleukin-5 metabolism, Kidney Neoplasms immunology, Leukocytes, Mononuclear immunology, Melanoma immunology
- Abstract
Sodium stibogluconate (SSG), an inhibitor of SHP-1 that negatively regulates cytokine signaling and immunity, suppressed growth of murine Renca tumors in combination with interleukin-2 (IL-2) via a T-cell-dependent mechanism. The ability of SSG to interact with IL-2 in activating primary human immune cells was evaluated herein by assessing its induction of interferon (IFN)-gamma(+) TH1 cells in human peripheral blood in vitro. The significance of IFN-gamma(+) cells was also investigated by assessing SSG/IL-2 antitumor activity in wild-type and IFN-gamma(-/-) mice. IFN-gamma(+) cells but not IL-5(+) cells were induced markedly (9.1x) in healthy peripheral blood by SSG/IL-2 in contrast to the modest induction by SSG alone (2.1x) at its clinically achievable dose (20 microg/mL) or by IL-2 (3.1x) at its C(max) of low-dose schedule (30 IU/mL). SSG at a higher dose (100 microg/mL) was less effective alone (1.5x) or in combination with IL-2 (7.8x). Peripheral IFN-gamma(+) cells were induced after 4 or 16 h treatment with SSG/IL-2 within CD4(+) and CD8(+) lymphocytes coincided with heightened CD69 expression (approximately 3-4x). SSG/IL-2 was also more effective than the single agents in inducing IFN-gamma(+) cells in the peripheral blood of melanoma patients, whose basal IFN-gamma(+) cell levels were approximately 5% of healthy controls. Renca tumor growth was inhibited by SSG/IL-2 in wild-type but not IFN-gamma(-/-) mice. These results demonstrate SSG interactions with IL-2 in vitro to activate key antitumor immune cells in peripheral blood of healthy and melanoma donors, providing further evidence for proof of concept clinical trials for effecting augmentation of IL-2 through inhibiting negative regulatory protein tyrosine phosphatases.
- Published
- 2009
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