No description available.

No description available.

No / Background: AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a prodrug which is selectively activated within hypoxic tissues to AQ4, a topoisomerase II inhibitor and DNA intercalator. Patients and methods: In the phase I study, 22 patients with oesophageal carcinoma received an i.v. infusion of AQ4N (22.5¿447 mg/m2) followed, 2 weeks later, by further infusion and radiotherapy. Pharmacokinetics and lymphocyte AQ4N and AQ4 levels were measured after the first dose. At 447 mg/m2, biopsies of tumour and normal tissue were taken after AQ4N administration. Results: Drug-related adverse events were blue discolouration of skin and urine, grade 2¿3 lymphopenia, grade 1¿3 fatigue, grade 1¿2 anaemia, leucopenia and nausea. There were no drug-related serious adverse events (SAEs). Three patients had reductions in tumour volume >50%, nine had stable disease. Pharmacokinetics indicated predictable clearance. Plasma area under the curve (AUC) at 447 mg/m2 exceeded AQ4N concentrations in mice at therapeutic doses and tumour biopsies contained concentrations of AQ4 greater than those in normal tissue. Tumour concentrations of AQ4 exceeded in vitro IC50 values for most cell lines investigated. Conclusions: No dose-limiting toxic effects were observed and a maximum tolerated dose was not established. Tumour AQ4 concentrations and plasma AUC at 447 mg/m2 exceeded active levels in preclinical models. This dose was chosen for future studies with radiotherapy.

This work presents an investigation of the potential development of phenoxodiol, a novel isoflavone, for the treatment of prostate cancer. The literature concerning isoflavone epidemiology, pharmacology, clinical use and their effect on prostate cancer is reviewed. Isoflavone impact on signal transduction pathways is also reviewed with a particular focus on the Akt / mTOR signal transduction pathway, a key signaling pathway in prostate cancer cells. In vitro experiments and xenograft nude mice studies show that phenoxodiol inhibits the growth of DU145 and PC3 prostate cancer cells, when used alone and in combination with cisplatin or carboplatin. Phenoxodiol in combination with cisplatin is highly synergistic when inhibiting the growth of DU145 cells in particular. We show for the first time, that phenoxodiol and cisplatin or carboplatin, inhibits phosphorylation of Akt and mTOR in DU145 and PC3 cells. A first-in-human study of single dose phenoxodiol investigating its pharmacokinetic properties in cancer patient volunteers was performed. Extensive conjugation of phenoxodiol and a short half-life was noted in this study. A Phase I study of intravenous phenoxodiol administered weekly to patients with advanced cancer was then performed to assess toxicity of a repeated dose schedule, as well as the maximum tolerated dose. This schedule was well tolerated in patients, with lymphocytopenia noted as the main toxicity. Given the short half-life of phenoxodiol and our preclinical studies suggesting that combination with cisplatin and carboplatin synergistically inhibited prostate cancer cell growth, we also undertook a Phase I dose escalation study of oral phenoxodiol administered in combination with cisplatin or carboplatin to patients with advanced cancer. The main adverse events include hyperglycemia, hypocalcemia, mild transaminase rises, as well as nausea, constipation, infusion site reactions and lethargy. Three patients with ovarian cancer responded to treatment according to CA125 criteria, and there was a 45% reduction in prostate specific antigen level in one man with androgen independent prostate cancer. The bioavailability of the oral formulation of phenoxodiol was calculated to be 17.5%. Phenoxodiol shows promise for further development in the potential treatment of prostate cancer.

This work presents an investigation of the potential development of phenoxodiol, a novel isoflavone, for the treatment of prostate cancer. The literature concerning isoflavone epidemiology, pharmacology, clinical use and their effect on prostate cancer is reviewed. Isoflavone impact on signal transduction pathways is also reviewed with a particular focus on the Akt / mTOR signal transduction pathway, a key signaling pathway in prostate cancer cells. In vitro experiments and xenograft nude mice studies show that phenoxodiol inhibits the growth of DU145 and PC3 prostate cancer cells, when used alone and in combination with cisplatin or carboplatin. Phenoxodiol in combination with cisplatin is highly synergistic when inhibiting the growth of DU145 cells in particular. We show for the first time, that phenoxodiol and cisplatin or carboplatin, inhibits phosphorylation of Akt and mTOR in DU145 and PC3 cells. A first-in-human study of single dose phenoxodiol investigating its pharmacokinetic properties in cancer patient volunteers was performed. Extensive conjugation of phenoxodiol and a short half-life was noted in this study. A Phase I study of intravenous phenoxodiol administered weekly to patients with advanced cancer was then performed to assess toxicity of a repeated dose schedule, as well as the maximum tolerated dose. This schedule was well tolerated in patients, with lymphocytopenia noted as the main toxicity. Given the short half-life of phenoxodiol and our preclinical studies suggesting that combination with cisplatin and carboplatin synergistically inhibited prostate cancer cell growth, we also undertook a Phase I dose escalation study of oral phenoxodiol administered in combination with cisplatin or carboplatin to patients with advanced cancer. The main adverse events include hyperglycemia, hypocalcemia, mild transaminase rises, as well as nausea, constipation, infusion site reactions and lethargy. Three patients with ovarian cancer responded to treatment according to CA125 criteria, and there was a 45% reduction in prostate specific antigen level in one man with androgen independent prostate cancer. The bioavailability of the oral formulation of phenoxodiol was calculated to be 17.5%. Phenoxodiol shows promise for further development in the potential treatment of prostate cancer.

Thesis (Ph. D.)--Virginia Commonwealth University, 2007. / Prepared for: Dept. of Biostatistics. Bibliography: leaves 179-181. Also available online via the Internet.

OBJECTIVE: The aim of this study was to investigate the safety and tolerability of a novel anti-folate drug, pemetrexed, in the setting of a phase I clinical trial in patients with non-HIV related central nervous system lymphoma (CNSL). METHODS: In this multicenter, open-label, phase I dose finding clinical trial, pemetrexed was investigated as a single agent treatment for primary or secondary CNSL. RESULTS: A total of 18 patients were enrolled between January 2009 and November 2014. The mean age was 64.6 years old (range: 47-79). The ratio of male to female was 1:1. One out of six patients experienced a dose limiting toxicity (DLT) at dose level 1 (600mg/m2). There were no DLTs among the four patients enrolled at dose level 2 (900m/m2). Two of six patients experienced a DLT at dose level 3 (1200mg/m2). The MTD was therefore determined to be 900mg/m2. Overall, pemetrexed was well tolerated but toxicities were seen and need to be monitored. All patients experienced at least one type of toxicity of any grade. Most patients (92.9%) experienced at least one type of neurological toxicity. Grade-3 toxicities included confusion, speech impairment, and psychosis. Twelve patients (85.7%) experienced at least one bone marrow type of toxicity of any grade. These toxicities included anemia (78.6%), thrombocytopenia (57.1%), neutropenia (50%), leukocytopenia (42.9%), and lymphopenia (42.9%). Four patients experienced either grade-3 (14.3%) or grade-4 (14.3%) neutropenia. Three patients experienced grade-3 leukopenia (21.4%). One patient experienced grade-3 lymphopenia (7.1%) and two patients experienced grade-4 lymphopenia (14.3%). Twelve patients (85.7%) experienced at least one metabolic type of toxicity of any grade. A majority of these were also grade-1 or 2, with the exception of hypophosphatemia (grade-4), hyperglycemia (grade-3) and increased ALT (grade-3), increased AST (grade-3) and increased creatinine phosphokinase (CPK) (grade-4). Constitutional and gastrointestinal symptoms were seen in >60% of patients. These consisted mainly of fatigue, constipation, nausea, and anorexia. Musculoskeletal symptoms were seen in greater than 60% of patients. Less common adverse events included pain (<60%), infection (<40%), dermatologic, ocular/visual, and pulmonary/upper respiratory (<30%). The average number of cycles on treatment for all patients was 5.5 cycles. 14 patients were evaluated for response to treatment by neuroimaging (MRI) while on treatment. Of these, four patients (28.6%) showed a complete response (CR). Of those patients, 2 patients achieved this response after only 2 doses, and 2 patients after a total of 8 doses. 5 patients (35.7%) showed a partial response (PR) and four patients (28.6%) achieved stable disease (SD). The overall response rate (ORR) was determined at 92.9% (SD, PR and CR combined). CONCLUSIONS: Given this data, pemetrexed is a powerful drug and feasible alternative to existing treatment options; however, certain toxicities need to be closely monitored. Further studies are needed to assess the efficacy of pemetrexed in a larger cohort of patients with CNSL.

No description available.

No description available.

Xenobiotics are plant derived compounds metabolized by phase I and II liver enzymes. Phase I enzymes increase, and phase II enzymes decrease, xenobiotic toxicity. Xenobiotics considered were ergotamine, associated with fescue toxicosis, and sulforaphane, a phase II inducer. Hypothesized responses in liver gene expression and enzyme activity due to exposure to these xenobiotics were tested. Polymorphic mice were gavaged with sulforaphane, ergotamine or control over four daily dosing periods (2, 5, 8 and 11 d), with at least 5 mice per treatment. Mice were killed and livers collected 24 h after last dosing. With ergotamine, expression of phase II genes catecholâ Oâ amine methyltransferase 1 (P = 0.009) on d 8, and glutathioneâ Sâ transferase (Gst) mu1 (Gstm1; P = 0.049) on d 11 was increased, and sulfotransferase 5a1 on d 11 decreased (P = 0.02). Sulforaphane increased expression of cytochrome P450 1a2 on d 5 (P = 0.02) and flavin containing monooxygenases 1 on d 11 (P = 0.002), both phase I genes. It also increased expression of a phase II gene transcription factor (P = 0.03) and quinone reductase 02 (P = 0.007) on d 5, and Gstm1 on d 8 (P = 0.04) and d 11 (P = 0.01). Moreover, sulforaphane treated mice had higher (P < 0.05) Gstm1 expression across days. Among enzymes, only sufloraphane treated mice had higher (P < 0.05) Gst activity. The increase in both Gstm1 expression and Gst activity indicate a consistent benefit of sufloraphane on phase II enzyme activity. / Master of Science