Clin Cancer Res
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Our objective was to determine the effect of neoadjuvant hormonal therapy on the presence of circulating prostate cells in patients undergoing radical prostatectomy for prostate cancer. A total of 60 patients at high risk for extraprostatic disease were analyzed for the presence of circulating prostate cells using reverse transcriptase PCR (RTPCR) amplification of the prostate-specific antigen mRNA. Twenty-nine patients underwent radical prostatectomy for a clinical T2b-c tumor or a stage T1c-T2a tumor and a serum prostate-specific antigen level > or =10ng/ml (radical prostatectomy alone), and 31 similarly staged patients received neoadjuvant hormonal therapy before radical prostatectomy (neoadjuvant). ⋯ These data suggest that a subset of the neoadjuvant patients are converted to organ confined disease without eliminating the prostate cells in the bone marrow. Our data suggest that hormonal therapy before radical prostatectomy decreases the occurrence of extraprostatic disease but, to a lesser degree, the incidence of circulating prostate cells. This may partially explain why hormonal therapy before radical prostatectomy has not improved disease-free survival.
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Multicenter Study Clinical Trial
Phase II trial of weekly paclitaxel and concurrent radiation therapy for locally advanced non-small cell lung cancer.
We conducted a prospective Phase II study to determine the response rate, toxicity, and 2-year survival rate of concurrent weekly paclitaxel and radiation therapy (RT) for locally advanced unresectable non-small cell lung cancer. The weekly paclitaxel regimen was designed to optimize the radiosensitizing properties of paclitaxel. Thirty-three patients with unresectable stage IIIA and IIIB non-small cell lung cancer from six institutions were entered into the study between March 1994 and February 1995. ⋯ Weekly paclitaxel plus concurrent RT is a well-tolerated outpatient regimen. The survival outcome from this regimen is encouraging and seems to be at least equivalent to that of other chemotherapy/radiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/RT in Phase II trials in the neoadjuvant setting and in combination with other cytotoxic agents.
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Randomized Controlled Trial Clinical Trial
Pharmacokinetics and bioavailability of oral 9-aminocamptothecin capsules in adult patients with solid tumors.
Preclinical studies indicate enhanced antitumor activity of 9-amino-20(S)-camptothecin (9-AC) when it is administered in a manner that provides prolonged systemic exposure. In view of this observation, the pharmacokinetics and oral bioavailability of 9-AC polyethylene glycol 1000 capsules were evaluated in 12 patients with solid tumors. ⋯ Plasma concentrations of the lactone and carboxylate forms of 9-AC rapidly reached an equilibrium, with the active lactone accounting for < 10% of total drug at the terminal disposition phase. The drug demonstrated peak levels at 1.2 h and an overall bioavailability of 48.6+/-17.6% (range, 24.5-80.4%), indicating significant systemic exposure to the drug, which may enable chronic oral treatment.
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The purpose of the present study was to characterize the distribution and elimination kinetics of the paclitaxel vehicle Cremophor EL (CrEL), a polyoxyethylated castor oil that can modulate P-glycoprotein-mediated multidrug resistance in vitro. The pharmacokinetics of CrEL were studied using noncompartmental models in 23 patients with histological proof of malignant solid tumors, receiving paclitaxel as a 3-h i.v. infusion at dose levels ranging from 100-225 mg/m2 (corresponding to CrEL doses of 8.33-18.8 ml/m2). Serial plasma samples were obtained before and up to 72 h after drug administration, and were analyzed for the presence of CrEL by a novel colorimetric dye-binding microassay. ⋯ The observed volume of distribution was extremely low and averaged 3.70+/-0.49 liters/m2, implying that the tumor delivery of CrEL is insignificant. Our results indicate that CrEL is a relatively slow clearance compound and that its distribution is limited to the central plasma compartment. Hence, CrEL is not likely to play a role in reversing P-glycoprotein-mediated multidrug resistance to paclitaxel in vivo.
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The expression of the polyamine catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), has been associated with tumor sensitivity to antitumor polyamine analogues. In the sensitive cell types the level of SSAT is greatly induced by these agents. Although SSAT expression is regulated at many levels, the initial regulation of this X-linked gene occurs at the level of transcription. ⋯ Most importantly, the H727 line expressed high amounts of SSAT mRNA and protein in response to treatment with the polyamine analogue, N1,N12-bis(ethyl)spermine, a compound known to increase SSAT transcription in sensitive cell types. H727 was also the only female line that responded to treatment in a cytotoxic manner. These data suggest that both copies of the SSAT allele may be expressed and that the inappropriate expression of the second copy can lead to an increase in tumor sensitivity to polyamine analogues that induce SSAT.