Showing papers by "Joel M. Reid published in 2004"
TL;DR: Gemcitabine given by 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks was tolerated well by children at doses of 2100 mg/m(2) and 1200 mg/ m(2), respectively.
Abstract: Purpose To determine the maximum tolerated dose, toxicity, and pharmacokinetics of gemcitabine in children with refractory solid tumors. Patients and Methods Gemcitabine was given as a 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks, to 42 patients aged 1 to 21 years. Doses of 1,000, 1,200 and 1,500 mg/m2 were administered for 3 weeks. Subsequently, gemcitabine was given for only 2 consecutive weeks at 1,500, 1,800, and 2,100 mg/m2. Plasma concentrations of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine, were measured in 28 patients. Results Forty patients who received 132 courses of gemcitabine were assessable for toxicity. The maximum tolerated dose of gemcitabine given weekly for 3 weeks was 1,200 mg/m2. Dose-limiting toxicity was not seen in one-third of children treated at any doses given for 2 weeks. The major toxicity was myelosuppression in three of five patients at 1,500 mg/m2 for 3 weeks, and one of seven patients at 1,800 mg/m2 for 2 weeks. Other serious adverse events ...
91 citations
TL;DR: Using capillary electrophoresis coupled with electrospray ionization mass spectrometry, three oxidative PZA metabolites are identified, 9-desmethyl-PZA, N-demethyl-Pza, and PZA N-oxide, which inhibited growth of A375 human melanoma cells and were detected in urine from patients after PZA administration.
Abstract: Pyrazoloacridine (PZA) is an experimental antitumor agent presently under investigation for treatment of solid tumors on the basis of its unique mechanism of action and selectivity for human solid tumor xenograft in mice. Using capillary electrophoresis coupled with electrospray ionization mass spectrometry, we have identified three oxidative PZA metabolites, 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide. The cytochrome p450 (CYP) isoforms involved in PZA metabolism were characterized by studies with CYP chemical inhibitors, correlation of marker activities for selected CYPs with formation of the metabolites using a human liver panel, and PZA metabolism by cDNA-expressed CYPs. 9-Desmethyl-PZA formation was catalyzed by CYP1A2, whereas N-demethyl-PZA formation was catalyzed by CYP3A4. PZA N-oxide formation was catalyzed by flavin monooxygenase (FMO) rather than CYP, as determined by studies with chemical inhibitors of FMO and metabolism by cDNA-expressed human flavin monooxygenase. After administration of [10b-(14)C]PZA to mice, six urinary metabolites were detected by high-performance liquid chromatography UV and radiochromatograms including 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide. Trace concentrations of 9-desmethyl-PZA and PZA N-oxide were detected in mouse plasma. PZA N-oxide and N-demethyl-PZA were detected in urine from patients after PZA administration. PZA, 9-desmethyl-PZA, and PZA N-oxide inhibited growth of A375 human melanoma cells. IC(50) values were 0.17, 0.11, and 7.0 micro M, respectively, for the three molecules.
31 citations
TL;DR: Results indicate that 17AAG is tolerable on a twice-weekly schedule and that at the MTD the drug affects the target in normal tissue.
Abstract: 3030 Background: Therapy directed at the molecular chaperone HSP90 causes degradation of multiple client proteins critical in cancer cell proliferation and survival. 17AAG, a HSP90 directed agent, has demonstrated in vitro and in vivo antitumor effects in a variety of cancers. Methods: We performed a phase I trial to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of 17AAG infused on days 1, 4, 8 and 11 of a 21 day cycle, to characterize the pharmacokinetics of 17AAG and its effect on chaperone and client proteins in peripheral blood mononuclear cells (PBMCs). An accelerated titration design was utilized. Surrogate markers were measured in PBMCs at baseline, day 1 and 4. Pharmacokinetic analysis was performed on day 1 only. Results: Twelve patients received 35 courses (median, 2) at 6 dose levels. Both patients treated at 308 mg/m2 experienced one or more of the non-hematologic DLTs: hyperglycemia, dehydration, diarrhea (with maximal supportive treatment), ALT, AST, and a...
22 citations
TL;DR: The MTD of this combination of OSI-774 and CPT-11 in patients with advanced solid tumors has not yet been determined and the DLTs appear related to presence of UGT1A1 polymorphisms.
Abstract: 3053 Background: We sought to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) of the combination of OSI-774 (an EGFR inhibitor) and CPT-11 in patients (pts) with advanced solid tumors. Secondary aims included pharmacokinetic evaluation for drug interactions and analysis of relationship between UGT1A1 genotype and toxicity. Methods: Eligibility criteria included presence of tumors known to overexpress EGFR, ECOG performance scores 0–2, adequate hematologic, renal and hepatic function. Therapy was with daily continuous oral OSI-774 and intravenous CPT-11 every 3 weeks (which started on day 7 of OSI-774 therapy in cycle 1). DLTs were defined as grade 4 neutropenia, grade 3 thrombocytopenia or ≥ grade 3 non-hematologic toxicities despite maximal supportive care. The presence of the UGT1A1*28 polymorphism (either 6/7 or 7/7 promoter TA repeats) was ascertained. Results: 19 pts (median age 62) were enrolled. Tumor primaries were colon/rectum (8), lung (7), ovary (2), esophagus...
3 citations