ABSTRACT
This case study evaluates the effects of a 4.7 mg deslorelin acetate implant on one male olive baboon (Papio anubis). Implantation induces transient azoospermia after which the subject was able to conceive again. Behavior was also impacted with a decrease in our proxies of aggressiveness and sexual arousal.
Subject(s)
Aggression/drug effects , Contraceptive Agents, Male/administration & dosage , Fertility/drug effects , Papio anubis/physiology , Sexual Behavior, Animal/drug effects , Social Behavior , Triptorelin Pamoate/analogs & derivatives , Animals , Contraception/veterinary , Contraceptive Agents, Male/pharmacology , Male , Triptorelin Pamoate/administration & dosage , Triptorelin Pamoate/pharmacologyABSTRACT
Vγ9Vδ2 T cells are attractive candidates for antileukemic activity. The analysis of Vγ9Vδ2 T cells in newly diagnosed acute myeloid leukemia (AML) patients revealed that their absolute cell numbers were normal in the blood as well as in the bone marrow but showed a striking imbalance in the differentiation subsets, with preponderance of the effector memory population. This unusual phenotype was restored after removal of leukemic cells in patients, which reached complete remission after chemotherapy, suggesting that leukemic cells might be involved in the alteration of γδ T cell development in AML. Accordingly, coculture between AML cells and Vγ9Vδ2 T cells induced selection of effector cells. In accordance with their effector memory status, in vitro proliferation of Vγ9Vδ2 T cells was reduced compared with normal controls. Nevertheless, Vγ9Vδ2 T cells efficiently killed autologous AML blasts via the perforin/granzyme pathway. The ligands for DNAM-1 were expressed by AML cells. We showed that killing of AML blasts was TCR and DNAM-1 dependent. Using a xenotransplantation murine model, we showed that Vγ9Vδ2 T cells homed to the bone marrow in close proximity of engrafted leukemic cells and enhanced survival. These data demonstrate that Vγ9Vδ2 T cells are endowed with the ability to interact with and eradicate AML blasts both in vitro and in a mouse model. Collectively, our data revealed that Vγ9Vδ2 T cells have a potent antileukemic activity provided that optimal activation is achieved, such as with synthetic TCR agonists. This study enhances the interest of these cells for therapeutic purposes such as AML treatment.
Subject(s)
Blast Crisis/immunology , Leukemia, Myeloid, Acute/immunology , Lymphocyte Activation , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocytes/immunology , Animals , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Antigens, Differentiation, T-Lymphocyte/immunology , Blast Crisis/metabolism , Blast Crisis/pathology , Blast Crisis/therapy , Female , Gene Expression Regulation, Leukemic/immunology , Granzymes/immunology , Granzymes/metabolism , Humans , Immunologic Memory , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Neoplasms, Experimental , Perforin/immunology , Perforin/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Transplantation, HeterologousABSTRACT
A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to >100 microM, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.
