[Combination of phenylbutyrate and 5-Aza-2'deoxycytidine inhibits human Kasumi-1 xenograft tumor growth in nude mice].
OBJECTIVE
To investigate the tumor suppression efficacy of histone deacetylase inhibitor, phenylbutyrate (PB), in combination with DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza-CdR) in the treatment of Kasumi-1 xenograft tumor in nude mice and its mechanism.


METHODS
The nude mice model of Kasumi-1 xenograft tumor was established by subcutaneous inoculation. Latency of tumor formation, the ability of Kasumi-1 cells pre treated with PB to form the xenograft tumor, and the tumor suppression activity of PB and 5-Aza-CdR by intraperitoneal injection in xenografted mice model were detected. Cell differentiation and cell cycle parameters of the tumor cells were analyzed by flow cytometry analysis, apoptosis by TUNEL in situ hybridization, and tumor microvessel density (MVD) by immunohistochemistry study.


RESULTS
The latency of tumor formation in mice with or without previous lienectomy was 17 approximately 23 and 40 approximately 50 days, respectively. Tumor cells xenografted could not be found in other tissues than in inoculation area, and still harbored the specific t(8;21) and AML1-ETO fusion gene. When the xenografted mice models treated with PB, 5-Aza-CdR, or both, the tumor growth inhibition rates were 49.07%, 25.69% and 87.46% (P < 0.05), the apoptosis indexes (AI) of tumor cells were (2.25 +/- 0.85)%, (1.32 +/- 0.68)%, and (5.41 +/- 1.56)% (P < 0.05), and the microvessel densities (MVD) were 21.69 +/- 6.25, 28.34 +/- 4.24 and 9.48 +/- 3.21 (P < 0.01), respectively. All the data above were significantly different from that in control (P < 0.05). The expression of CD11b and CD13 antigen of the tumor cells was increased in xenografted mice model treated with PB when compared with the control \[(12.08 +/- 1.02)% and (54.91 +/- 2.72)%\], respectively (P < 0.01), and tumor cells showed a cell cycle arrest with increased G(0)/G(1)-phase cells and decreased S-phase cells.


CONCLUSIONS
PB inhibited the growth of Kasumi-1 xenograft tumor by inducing tumor cell apoptosis and differentiation, and suppressing its angiogenesis in vivo. 5-Aza-CdR could significantly enhance the antitumor activity of PB.
Hao
Chang-lai
CL
Institute of Hematology, CAMS&PUMC, Tianjin 300020, China.
Lin
Dong
D
Wang
Li-hong
LH
Xing
Hai-yan
HY
Wang
Min
M
Wang
Jian-Xiang
JX
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010654:Phenylbutyrates / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D010654:Phenylbutyrates; D003841:Deoxycytidine; C075773:4-phenylbutyric acid