JTE-607, a multiple cytokine production inhibitor, ameliorates disease in a SCID mouse xenograft acute myeloid leukemia model

Uesato, Naofumi; Fukui, Kenji; Maruhashi, Junji; Tojo, Arinobu; Tajima, Nobuyuki

doi:10.1016/j.exphem.2006.05.016

« Previous Next »Experimental Hematology
Volume 34, Issue 10 , Pages 1385-1392, October 2006

JTE-607, a multiple cytokine production inhibitor, ameliorates disease in a SCID mouse xenograft acute myeloid leukemia model

Naofumi Uesato
- Biological and Pharmacological Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
- Offprint requests to: Naofumi Uesato, Biological and Pharmacological Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
Kenji Fukui
- Biological and Pharmacological Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
Junji Maruhashi
- Biological and Pharmacological Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
Arinobu Tojo
- Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Nobuyuki Tajima
- Biological and Pharmacological Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan

Received 9 March 2006; received in revised form 16 May 2006; accepted 25 May 2006.

Objective

Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model.

Methods

SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45⁺ cells in the bone marrow were studied.

Results

The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45⁺ cells. Human IL-8 level was also reduced by JTE-607.

Conclusion

Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.