Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin.
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We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered. (+info)
MRP3, an organic anion transporter able to transport anti-cancer drugs.
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The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2. In Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane and mediates transport of the organic anion S-(2,4-dinitrophenyl-)glutathione toward the basolateral side of the monolayer. In ovarian carcinoma cells (2008), expression of MRP3 results in low-level resistance to the epipodophyllotoxins etoposide and teniposide. In short-term drug exposure experiments, MRP3 also confers high-level resistance to methotrexate. Neither 2008 cells nor Madin-Darby canine kidney II cells overexpressing MRP3 showed an increase in glutathione export or a decrease in the level of intracellular glutathione, in contrast to cells overexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells. (+info)
Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress.
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Hydrogen peroxide (H2O2), a reactive oxygen species (ROS), is known to induce oxidative stress and apoptosis. U937 cells treated with H2O2 were shown to produce high molecular weight (HMW) DNA fragments approximately 50 to 100 kb in size in <1 min. The formation of these HMW DNA fragments is reversible and shown to be mediated by DNA topoisomerase II (TOP2). Following this initial event, formation of irreversible HMW DNA fragments and nucleosomal ladders occurs. Our results thus demonstrate a potential role of TOP2 in oxidative damage of DNA and apoptotic cell death. (+info)
Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte.
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PURPOSE: To identify the prognostic factors that influence overall survival (OS) in patients with stage III-IV follicular lymphomas and evaluate the clinical usefulness and the prognostic value of the International Prognostic Index (IPI). PATIENTS AND METHODS: Four hundred eighty-four patients with Ann Arbor stage III-IV follicular lymphomas treated in two phase III trials from 1986 to 1995 were screened for this study. All histologic slides were reviewed by two hematopathologists. The influence of the initial parameters on survival was defined by univariate (log-rank test) and multivariate (Cox model) analyses. RESULTS: The poor prognostic factors for OS (age > 60 years, "B" symptom(s), > or = two extranodal sites, stage IV disease, tumor bulk > 7 cm, at least three nodal sites > 3 cm, liver involvement, serous effusion-compression or orbital/epidural involvement, and erythrocyte sedimentation rate > 30 mm/h) that were significant in univariate analysis were subjected to multivariate analysis. Three factors remained significant: B symptom(s) (risk ratio = 1.80), age greater than 60 years (risk ratio = 1.60), and at least three nodal sites greater than 3 cm (risk ratio = 1.71). When the IPI was applied to these patients, the score was 1, 2, 3, and 4-5 in 49%, 39%, 11%, and 2%, respectively, and it was significant for progression-free survival (P =.002) and OS (P =.0001). CONCLUSION: Three prognostic factors for poor OS were identified: B symptoms, age greater than 60 years, and at least three nodal sites greater than 3 cm. The IPI was prognostic for OS, but in this population, a very low number of patients belonged to the high-risk groups. (+info)
Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: a GELA study. Groupe d'Etudes des Lymphomes de l'Adulte.
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BACKGROUND: Fludarabine was associated with a good response and was well tolerated in patients with follicular lymphoma in phase II trials and this treatment may be associated with less adverse events than treatment with CHVP plus interferon in elderly patients. PATIENTS AND METHODS: One hundred thirty-one patients older than 59 years with a follicular lymphoma and poor prognosis were randomized between the association of CHVP (12 cycles in 18 months) plus interferon (5 MU TIW for 18 months) or fludarabine alone (25 mg/m2/d x 5 days for 6 cycles, then 20 mg/m2/day for 6 further cycles for 18 months). Poor prognosis was defined by the presence of a large tumor mass, poor performance status, the presence of B symptoms, above normal LDH level, or > or = 3 mg/l beta-microglobulin level. RESULTS: Patients treated with CHVP plus interferon had a higher response to treatment, a longer time to progression and a longer survival than those treated with fludarabine alone (P < 0.05 for all analyses). With a median follow-up of 29 months, the 2-year failure-free survival was 63% for the CHVP-plus-interferon arm compared to 49% for the fludarabine arm and the two-year survival was 77% and 62%, respectively. This benefit was confirmed in a multivariate analysis including initial prognostic parameters. Fludarabine alone was associated with less neutropenia than CHVP plus interferon. Interferon was decreased or stopped in 39% of the patients because of severe fatigue. CONCLUSIONS: CHVP plus interferon over 18 months was associated with a better outcome, even though the combination of interferon plus chemotherapy was less well tolerated than fludarabine. (+info)
SUMO-1 conjugation to human DNA topoisomerase II isozymes.
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Topoisomerase I-mediated DNA damage induced by camptothecin has been shown to induce rapid small ubiquitin-related modifier (SUMO)-1 conjugation to topoisomerase I. In the current study, we show that topoisomerase II-mediated DNA damage induced by teniposide (VM-26) results in the formation of high molecular weight conjugates of both topoisomerase IIalpha and IIbeta isozymes in HeLa cells. Immunological characterization of these conjugates suggests that both topoisomerase IIalpha and IIbeta isozymes are conjugated to SUMO-1. The involvement of SUMO-1/UBC9 in the modification of topoisomerase II isozymes is also supported by the demonstration of physical interaction between topoisomerase II and SUMO-1/UBC9. Surprisingly, ICRF-193, which does not induce topoisomerase II-mediated DNA damage but traps topoisomerase II into a circular clamp conformation, is also shown to induce similar SUMO-1 conjugation to topoisomerase II isozymes. In addition, we show that both oxidative and heat shock stresses, which can cause protein damage, rapidly increase nuclear SUMO-1 conjugates. These studies raise the question on whether SUMO-1 conjugation to topoisomerases is an indirect result of a DNA damage response or a direct result because of protein conformational changes. (+info)
Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group.
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PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m(2) was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P<.001). Time to progression in the brain was longer in the combined-modality group (P=.005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P=.087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different. (+info)
Differences in mutant p53 protein stability and functional activity in teniposide-sensitive and -resistant human leukemic CEM cells.
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We examined p53 protein stability and DNA damage-induced p53-dependent responses in a human leukemic CEM cell line and two teniposide-resistant sublines, CEM/VM-1 and CEM/VM-1-5 ( approximately 40 and 400-fold resistant to teniposide, respectively). Although all cell lines contain the same p53 mutations at codons 175 (Arg-->His) and 248 (Arg-->Gln), the constitutive levels of p53 were progressively increased with the resistance of the cells to teniposide. By pulse-chase experiments, we found that the half-lives of mutant p53 protein were approximately 12, 17, and >30 h in CEM, CEM/VM-1, and CEM/VM-1-5 cells, respectively. The prolonged half-lives of p53 in these cells is consistent with the fact that the protein harbors the indicated mutations. Of note, however, is the fact that the increased p53 protein half-lives in the two drug-resistant cell lines corresponds to a proportional decrease in MDM2 protein levels but an increase in p53-MDM2 binding interactions. This suggests that MDM2-mediated p53 degradation may be altered in our leukemic cell lines. The DNA damage-induced p53 response is fully functional in the drug-sensitive CEM cells containing a mutant p53, but this pathway is attenuated in the drug-resistant cells. Specifically, while the mutant p53 was phosphorylated at serine-15 in response to ionizing radiation in all these cell lines, mutant p53 induction in response to teniposide or ionizing radiation and induction of the p53-target genes, p21 and GADD45 only occurred in the drug-sensitive CEM cells. As assessed by MTT cytotoxicity assay, CEM cells were also significantly more sensitive to ionizing radiation, compared to the drug-resistant cell lines, and this correlated with p53 induction. Collectively, these results suggest that changes in constitutive mutant p53 protein levels, p53-MDM2 binding interactions, and altered regulation of the DNA damage-inducible p53-dependent pathway may play a role in drug- and radiation-responsiveness in these cells. (+info)