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¹ Division of Hematology and Oncology, Karmanos Cancer Institute; ² Departments of Pathology and Internal Medicine, Wayne State University School of Medicine, Detroit, MI; and ³ National Center for Toxicology Research, FDA, Jefferson, AR

Requests for Reprints: Ramzi M. Mohammad, Division of Hematology and Oncology, Department of Internal Medicine/Karmanos Cancer Institute, Wayne State University School of Medicine, 724 HWCRC, 4100 John R Street, Detroit, MI 48201. Phone: (313) 966-7427; Fax: (313) 966-7558. E-mail: Mohammad{at}karmanos.org

The incidence of non-Hodgkin's lymphoma (NHL) has been increasing and is now the leading cause of death in males aged 15–54. Diffuse large cell lymphoma (DLCL) is the most common subtype of NHL. These cells are notable for the high expression of the transcription factor nuclear factor kappa beta (NF-B), raising the possibility that constitutive activation of the NF-B pathway may contribute to the poor prognosis of DLCL patients. Soy isoflavone genistein promotes apoptosis by decreasing NF-B activity. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the standard therapy for DLCL with a cure rate of 40%. The WSU-DLCL₂ cell line and its severe combined immunodeficient (SCID) xenograft have constitutively active NF-B which provides us with an excellent model in which to study NF-B modulation and CHOP sensitization by genistein. The antitumor activity of CHOP with or without a genistein was evaluated in our WSU-DLCL₂ model. In vivo, WSU-DLCL₂-bearing SCID mice received genistein alone (800 µg kg^-1 day^-1, p.o. as gavages for 5 days), CHOP alone ("C", 40 mg/kg, i.v.; "H", 3.3 mg/kg, i.v.; "O", 0.5 mg/kg, i.v.; and "P", 0.2 mg/kg, every day for 5 days, p.o.), or genistein for 5 days followed by CHOP. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log₁₀ kill for genistein, CHOP, and genistein followed by CHOP were 33.6%, 19.2%, and 5.2%; 7, 8, and 17 days; and 1.0, 1.2, and 2.6, respectively. To begin elucidating the mechanism of genistein-induced sensitization of WSU-DLCL₂ cells to CHOP chemotherapy in this xenograft mouse model, we studied the in vitro effect of genistein on WSU-DLCL₂ growth inhibition, cell cycle, Bax:Bcl-2 ratio, NF-B DNA binding, and apoptosis in vitro. At 30 µM, genistein inhibited the growth significantly, induced G₂-M arrest, increased Bax:Bcl-2 ratio, decreased NF-B DNA binding, and induced apoptosis. Genistein also inhibited NF-B DNA binding in vivo, whereas CHOP enhanced it. Our results show that genistein has growth modulatory effects on WSU-DLCL₂ cells and enhances the antitumor activity of CHOP. Because soy isoflavone genistein is a widely available nutritional supplement, its use in combination with CHOP chemotherapy should be further explored in a clinical trial in patients with NHL.

Key Words: B-cell • DLCL • Genistein • Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) • Xenografts

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support: National Institutes of Health Grant P30 CA22453-20.

Received 6/25/03; revised 9/12/03; accepted 9/15/03.

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