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Effects of 4-Amino-2-Trifluoromethyl-Phenyl Retinate on Human Leukemia Mouse Model and Tts Influence on Retinoid Acid Receptors and Retinoid X Receptors

Author: ChenHuiHui
Tutor: ChenFeiHu
School: Anhui Medical University,
Course: Pharmacology
Keywords: Leukemia All-trans retinoic acid 4 - amino - 2 - (trifluoromethyl) phenyl retinoic acid ester NB4 cells Leukemia animal model Induced differentiation Retinoic acid receptor Retinoid X receptor
CLC: R733.7
Type: Master's thesis
Year: 2011
Downloads: 69
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Abstract


Induction of differentiation therapy is a new breakthrough in the treatment of malignant tumors, and that the presence of the in vitro and in vivo differentiation inducer, tumor cells tend differentiation and maturation, to the normal direction is reversed, thereby restoring normal cell phenotype and function. Retinoic acid compound that is a model of differentiation-inducing agents. Our group early lead compound all-trans retinoic acid (all-trans retinoic acid, ATRA), the structural modification of the structural transformation and the end of the carbon chain polar groups of the cyclohexene ring, from the synthesized New retinoic acid derivatives screened 4 - amino-2 - trifluoromethylphenyl retinoic acid ester (4-amino-2-trifluoromethyl-phenyl retinate, ATPR) on acute promyelocytic leukemia cells line NB4 strong differentiation-inducing activity. This article will use the non-obese diabetic / severe combined immunodeficiency (non-obese diabetic / severe combined immunodeficiency or NOD / SCID) mice replication leukemia model is to observe the ATPR in vivo pharmacology leukemia, further evaluation of its efficacy, and discuss retinoic acid receptor and retinoid X receptor 4 - amino-2-- trifluoromethylphenyl retinoic acid ester induced NB4 cell differentiation mechanism to further elucidate the efficacy play. Objective: This study was designed to investigate the novel retinoic acid derivatives ATPR therapeutic effect of transplanted human leukemia mouse model NB4 cell differentiation induced by retinoic acid receptors and retinoid X receptor changes. Method :6-7-week-old NOD / SCID mice of the weight of 18-22g on the the SPF grade Laboratory of the Animal Center of Anhui adaptation one week after receiving 2.5Gy body X-ray irradiation, within 24 hours after irradiation, and the third days taken for transplantation logarithmic phase NB4 cells (3 × 106 /). NOD / SCID mice were randomly divided into six groups: the blank radiological control group, model group, ATRA group (10mg/kg) ATPR group (5mg/kg, 10mg/kg, 20mg/kg). Mice by intraperitoneal injection of the control group and the model group, polyoxyethylene castor oil (solvent), the dosing group modeled after intraperitoneal injection of the appropriate dose of drug 7d, every administered once a day for four consecutive weeks. Daily observation and recording of animal deaths, and weighing the body weight of the mice in each group; administration after detection of mouse ascites tumor cells indicators: (1) nested RT-PCR analysis of PML-RARα gene in ascites tumor cells; ② karyotype analysis of ascites tumor cells and the NB4 cells chromosomes; ③ the inverted microscope ascites cell differentiation morphological observation; ④ NBT reduction experimental analysis of differentiation ascites cells percentage. Were assayed solid tumor cells indicators: ① flow cytometer detection of abdominal aneurysm, CD45, CD33, CD11b-positive rate; ② flow cytometer detection each group of mice solid tumor cell cycle; (3) removal of abdominal solid tumors, HE staining observed morphological changes. Investigation of the wettability of the tumor cells in vivo changes in: (1) Statistics mouse body weight; ② flow cytometer detection of liver, spleen, kidney, lung CD45, CD33 positive rate; ③ flow cytometry to detect the mouse liver, spleen cell cycle; ④ take the liver, spleen, kidney, lung, heart, brain, bone marrow, and to 10% formaldehyde, 48 hours, paraffin-embedded sections, HE staining observed by light microscopy; the ⑤ statistical survival Days calculate the rate of life-prolonging. Mechanism: (1) by RT-PCR, Western Blot technology detects ATPR NB4 cells induced RARα expression in MSC, RARβ, RARγ of RXRα RXRβ RXRγmRNA and PML / RARα, RARβ and RARγ protein expression changes; (2) using immunohistochemical detection ATPR leukemia in mice tumor tissues RARβ, RARγ, RXRα role. Results: 1 in established leukemia animal model, NB4 cells can be varying degrees of infiltration into the tissues and organs such as the liver, spleen, kidney, lung, successful modeling. 2 ATPR APL-NOD/SCID model mouse ascites tumor cells induced to differentiate: ATPR induced ascites tumor cells to granulocyte differentiation and maturation of change; NBT positive rate of increase. Abdominal solid tumor mouse model of APL-NOD/SCID 3 ATPR differentiation-inducing effect: the tumor cell surface differentiation antigens CD11b expression was significantly increased; Tumor Cell Cycle in G0/G1 phase cells increased significantly was the G0/G1 phase resistance stagnation; pathological examination revealed the tumor cells to granulocyte differentiation and maturation of change. 4 ATPR can reduce the degree of infiltration in vivo APL-NOD/SCID model mice: liver, spleen, kidney, lung and major organizations such as CD45, CD33 positive rates varying degrees of reduction; proliferative phase of the liver and spleen (G2-MS Phase) The cells reduced; pathological examination also found that the degree of infiltration has been reduced. NB4 after 5 ATPR role, cells RARα expression in MSC, the RARβ, RARγmRNA express the amount of increases, and was time-dependent relationship, RXRα, RXRβ, RXRγmRNA expression amount without significantly with sex change; PML / of RARα fusion protein expression significantly with reducing, RARβ and RARγ protein expression increased significantly and was time-dependent; ATPR also elevated leukemia mice tumor tissue RARβ and RARγ protein expression of no effect on RXRα. 6 ATPR 5mg/kg, 10mg/kg, 20mg/kg three doses can extend the survival period of APL-NOD/SCID model mice. Conclusion: to accept sublethal radiation NOD / SCID mice by intraperitoneal injection of 3 × 10 ~ 6 NB4 cells the APL model can be successfully established. The 2 new retinoic acid derivative ATPR so ascites tumor and solid tumor cell differentiation and maturation of myeloid to reduce leukemia cells in vivo invasive. The 3 new retinoic acid derivative ATPR can significantly prolong the survival of APL mouse model. For NB4 cells 4 ATPR efficacy play a major role similar mechanism with ATRA, combined with RARs that is, on the one hand in the intracellular formation of RAR / RXR heterodimer with the retinoic acid response element (RARE) binding, thereby regulating gene transcription and translation, on the other hand degradation of the PML / RARα fusion protein in NB4 cells, activation of reliance on the RXRα nuclear hormone differentiation pathway NB4 cells tend to be divided mature.

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CLC: > Medicine, health > Oncology > Hematopoietic and lymphoid neoplasms > Leukemia
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