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L Zwelling

Publications and source records attributed to L Zwelling.

4 recordsLinked to original sources
PubMed1995

Topotecan in chronic lymphocytic leukemia.

BACKGROUND: Topotecan is one of a new class of agents that targets topoisomerase I (Topo I) and stabilizes the DNA-topo1 complex, ultimately resulting in cell death. The rationale for the use of topotecan in chronic lymphocytic leukemia (CLL) is based on the finding that levels of Topo I are elevated in the lymphocytes of patients with this disease. METHODS: Twelve patients with CLL were treated with topotecan to assess its clinical efficacy; in addition, DNA-protein cross-linking was measured after exposure of the cells to topotecan, in an attempt to correlate potential anti-CLL effects with this parameter. The median age of the patients was 63 years; all had received prior therapy with fludarabine and four (33%) were resistant to fludarabine. Four patients (33%) had also received therapy with chlorambucil, and three of them were resistant to this agent. Seven patients (58%) were Rai stage I-II and five (42%) were Rai stage III-IV. Topotecan was given as a 30-minute infusion at a daily dose of 2 mg/m2 for 5 days, and courses were repeated monthly. Cells were obtained from the patients before treatment and exposed to 2 microM topotecan or control in vitro. In addition, cells were obtained from patients after they received the first dose of topotecan and protein-bound DNA was measured with the same technique. RESULTS: No patient responded to therapy with topotecan (95% confidence interval, 0-27%). Nonhematologic toxicity was mild and thrombocytopenia occurred in four of eight patients whose conditions could be evaluated. One patients died of myocardial infarction and another died of fungal pneumonia. DNA-protein cross-linking was detected in all nine patients whose cells were assessed in vitro, with levels of cleavable complex ranging from twofold to 7.5-fold that of the control cells. Only two of eight patients with evaluable conditions had increased cross-linking detectable in circulating cells after the first dose of topotecan, which was consistent with the drug's lack of effect in vivo. CONCLUSIONS: Although exposure of cells from patients with CLL to topotecan in vitro at 2 microM resulted in detectable protein-DNA cross-linking, this effect was not seen in patients who received a bolus dose of 2 mg/m2, and no remissions were noted in 12 patients.

Adult↗
PubMed1993

Altered phosphorylation, biosynthesis and degradation of the 170 kDa isoform of topoisomerase II in amsacrine-resistant human leukemia cells.

Resistance to amsacrine in HL-60/AMSA is 50-100 fold compared to the parental HL-60/S cells. Synthesis and phosphorylation of topoisomerase II (TOPO II) were 2-3 fold lower in HL-60/AMSA compared to HL-60/S cells metabolically labelled with [32P]-orthophosphoric acid or [35S]-L-methionine. Incubating cells in radiolabel-free media following metabolic labelling for 4 hr revealed: (a) dephosphorylation of topoisomerase II at 4 hr was 70% and 20% in HL-60/S and HL-60/AMSA cells, respectively; and (b) degradation of topoisomerase II at 4 hr was 40% and 10% in HL-60/S and HL-60/AMSA cells, respectively, while at 8 hr degradation was 80% and 50% in HL-60/S and HL-60/AMSA cells, respectively. The magnitude of topoisomerase II band depletion in immunoprecipitates of amsacrine-treated cells labelled with [35S]-L-methionine or [32P]-orthophosphoric acid, correlated with the differential amsacrine sensitivity of HL-60/S and HL-60/AMSA cells, suggesting that the amount of newly synthesized and phosphorylated topoisomerase II may be contributing to amsacrine resistance. Thus, the attenuated synthesis and phosphorylation of TOPO II in HL-60/AMSA may contribute to the resistance of these cells to amsacrine.

Amsacrine↗
PubMed1993

Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia.

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Acute Disease↗