Increases in NMR-visible lipid and glycerophosphocholine during phenylbutyrate-induced apoptosis in human prostate cancer cells.

DU145 human prostatic carcinoma cells were treated with the differentiating agents phenylacetate (PA) and phenylbutyrate (PB) and examined in perfused cultures by diffusion-weighted 1H and 31P nuclear magnetic resonance spectroscopy (NMR). PA and PB (10 mM) induced significant (>3-fold) time-dependent increases in the level of NMR-visible lipids and total choline in 1H spectra, and glycerophosphocholine levels in the 31P spectra, with the increases being greater for PB. These effects were accompanied by significant increases in cytoplasmic lipid droplets and intracellular lipid volume fraction as observed by morphometric analysis of Oil Red O-stained cells. PB treatment caused cell cycle arrest in the G1 phase and induction of apoptosis. In contrast, PA-treated DU145 cells showed an accumulation of cells in G2/M and no evidence of apoptosis. These results demonstrate that significant differences exist in the mechanism of PA and PB activity, although both compounds cause similar, but graded alterations in lipid metabolism. The simultaneous accumulation of mobile lipid and glycerophosphocholine suggests that PB and PA induce phospholipid catabolism via a phospholipase-mediated pathway. The mobile lipid accumulation following the induction of either apoptosis and cytostasis by related differentiating agents indicate that the presence of NMR-visible lipids may not be a specific event causally resulting from the induction of apoptosis.

Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma.

PURPOSE: Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy. PATIENTS AND METHODS: According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m(2) twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment. RESULTS: Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88-289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths. CONCLUSION: Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.

Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study.

PURPOSE: The goal of this multicenter, open-label phase II study was the clinical evaluation of combination therapy with the oral fluoropyrimidine capecitabine and the taxane paclitaxel in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-seven patients with MBC received oral capecitabine at 1650 mg/m(2)/d (825 mg/m(2) twice daily) on days 1 through 14, and intravenous infusion of paclitaxel at 175 mg/m(2) on day 1 of each 21-day treatment cycle. Treatment continued until disease progression, intolerable toxicity, or patient' s decision to discontinue. Patients (35 to 76 years old) had a median Karnofsky performance status of 90%. Forty-four patients (94%) received study treatment as first-line therapy for metastatic disease. RESULTS: Objective responses occurred in 24 (51%) patients; seven (15%) complete responses and 17 (36%) partial responses. Stable disease lasting 180 days or more was observed in nine (19%); the clinical response rate was 70%. Median duration of response was 12.6 months, median time to disease progression was 10.6 months, and median overall survival time was 29.9 months. The most common treatment-related adverse events, regardless of severity, were alopecia, hand-foot syndrome, nausea, and fatigue. Neutropenia (15%), alopecia (13%), and hand-foot syndrome (11%) were the only grade 3 or 4 treatment-related adverse events that occurred in more than 10% of patients. CONCLUSION: The combination of capecitabine plus paclitaxel is a highly active and generally well-tolerated regimen for first-line treatment of MBC.