A novel therapeutic approach for hematological malignancies based on cellular differentiation and apoptosis
Recent Advances for Management of Hematologic Malignancies
Hematological malignancies including acute leukemia, and multiple myeloma are disorders characterized by the accumulation of neoplastic hematopoietic cells, resulting in aggressive clinical manifestations with poor prognosis. The therapeutic approach to these disorders is basically chemotherapy for achieving complete remission based on the concept of total cell kill. However, severe side effects and complications such as serious infection and bleeding due to anti-cancer drugs are major problems in the clinical setting. In addition, repeated episodes, of relapse of the disease may lead to refractory or chemotherapy-resistant disorders. These problems are occurred because anti-cancer agents have effects on both cancer cells and normal hematopoietic cells. The clinical evidences thus suggest the limitations of the chemotherapy for hematological malignancies: novel effective therapeutic approaches with less toxicity are therefore actively being sought. Differentiation-inducing therapy employing a physiologically active derivative of vitamin A, all-trans retinoic acid (ATRA), brought remarkably advances in the therapeutic outcome of APL at the end of last century. More recently, the clinical success of imatinib mesylate (STI571), potent competitive inhibitor of the Bcr/Abl protein tyrosine kinase, in the treatment of CML has focused enthusiasm toward molecular targeted therapy for the hematological malignancies. The therapeutic activity of these agents can be explained by their abilities to modify cellular growth, differentiation, and apoptosis in cells by activating unknown gene programs that molecular cellular proliferation. We have actively sought out new agents among natural products and cytokines with the ability to induce cellular differentiation and apoptosis. In this symposium, I will present our recent data of these novel compounds and their molecular mechanisms for inducing differentiation and apoptosis of hematological malignant cells. *** DIRECT SUPPORT *** A00RC002 00012
KeywordsMultiple Myeloma Chronic Myeloid Leukemia Capsaicin Hematological Malignancy EGCG
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: new mechanisms, strategies, and implications.Blood.
Goldman JM, Melo JV. Targeting the Bcr-Abl tyrosine-kinase in chronic myeloid leukemia.N Engl J Med.
. 2001;344: 1084–1086.PubMedCrossRefGoogle Scholar
Kizaki M, Ueno Y, Yamazoe M, et al. Mechanisms of retinoid resistance in leukemic cells: Possible role of cytochrome P450 and P-glycoprotein.Blood.
Takayama N, Kizaki M, Hida T, Kinjo K, Ikeda Y. A novel mutation in the PML/RAPa chimeric gene exhibits dramatically decreased ligand-binding activity and confers acquired resistance to retinoic acid in acute promyelocytic leukemia.Exp Hematol.
Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplication.Science.
Fukuchi Y, Kizaki M, Kinjo K, et al. Establishment of a retinoic acid resistant acute promyelocytic leukemia model in hGM-CSF transgenic SCID mice.Br J Cancer.
Yamato K, Hashimoto S, Okahashi N, et al. Dissociation of bone morphogenetic protein-mediated growth arrest and apoptosis of mouse B cells by HPV-16 E6/E7.Exp Cell Res.
Yamato K, Hashimoto S, Imamura T, et al. Activation of p21CIP1/KIP1
promoter by bone morphogenetic protein-2 in mouse B lineage cells.Oncogene.
Kawamura C, Kizaki M, Yamato K, et al. Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells with modulation of STAT3.Blood.
Kawamura C, Kizaki M, Ikeda Y. Bone morphogenetic protein (BMP)-2 induces apoptosis of human myeloma cells.Leuk Lymphoma.
Pisters AMW, Newman RA, Coldman B, et al. Phase I trial of oral green tea extract in adult patients with solid tumors.J Clin Oncol.
Kizaki M, Matsushita H, Takayama N, et al. Establishment and characterization of a novel acute promyelocytic leukemia cell line (UF-1) with retinoic acid resistant features.Blood.
Kinjo K, Kizaki M, Nuto A, et al. Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice.Leukemia.
Muto A, Kizaki M, Kawamura C, et al. A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF.Leukemia.
2001; 15:1176–1184.PubMedCrossRefGoogle Scholar
© The Japanese Society of Hematology 2002