Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.
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PMID:Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies. 1058 90

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-kappaB), raising the possibility that constitutive activation of the NF-kappaB pathway may contribute to the poor prognosis of DLCL patients. Soy isoflavone genistein promotes apoptosis by decreasing NF-kappaB activity. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the standard therapy for DLCL with a cure rate of approximately 40%. The WSU-DLCL(2) cell line and its severe combined immunodeficient (SCID) xenograft have constitutively active NF-kappaB which provides us with an excellent model in which to study NF-kappaB modulation and CHOP sensitization by genistein. The antitumor activity of CHOP with or without a genistein was evaluated in our WSU-DLCL(2) model. In vivo, WSU-DLCL(2)-bearing SCID mice received genistein alone (800 micro g 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 log(10) 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-DLCL(2) cells to CHOP chemotherapy in this xenograft mouse model, we studied the in vitro effect of genistein on WSU-DLCL(2) growth inhibition, cell cycle, Bax:Bcl-2 ratio, NF-kappaB DNA binding, and apoptosis in vitro. At 30 micro M, genistein inhibited the growth significantly, induced G(2)-M arrest, increased Bax:Bcl-2 ratio, decreased NF-kappaB DNA binding, and induced apoptosis. Genistein also inhibited NF-kappaB DNA binding in vivo, whereas CHOP enhanced it. Our results show that genistein has growth modulatory effects on WSU-DLCL(2) 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.
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PMID:Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. 1470 77