BACKGROUND The magnitude of chemotherapy dose escalation made possible by the use of recombinant haematopoietic growth factors has not been quantified in a randomized trial. PATIENTS AND METHODS Patients with refractory or relapsing Hodgkin's disease were randomized to receive the Dexa-BEAM regimen with escalating etoposide doses supported by placebo or granulocyte-macrophage colony-stimulati...

In an effort to shed light upon the processes of antitumor drug-induced cell death, we have carried out a systemic study of the effects of the anti-topoisomerase II agent, etoposide, on Chinese hamster ovary cells. Treatment of Chinese hamster ovary cells for 1 h with a 2-log cell-killing concentration of etoposide induces a high incidence of DNA single-strand breaks which are rapidly repaired ...

II.M"''kinase, an enzyme essential for mitosis in mammalian cells, may play a role in etoposide-induced G2 phase arrest of Chinese hamster ovary cells. In this study, etoposide is shown to cause inhibition of a specific p3-4"''-'kinase activation pathway, that of tyrosine dephosphorylation. Exposure of asynchronous!}' dividing cells to etoposide caused a simultaneous rapid decline of both mitot...

Topoisomerase II-catalyzed DNA transport requires coordination between two distinct reactions: ATP hydrolysis and DNA cleavage/religation. To further understand how these reactions are coupled, inhibition by the clinically used anticancer drug etoposide was studied. The IC(50) for perturbing the DNA cleavage/religation equilibrium is nucleotide-dependent; its value is 6 microM in the presence o...

Etoposide and cytarabine have been shown to exert high antileukemic activity and are currently under study as preparatory agents before allogeneic bone marrow transplantation. However, data concerning their engraftment-promoting potency are scarce. Therefore, we tested these agents in LEW rats receiving a myeloablative dose of busulfan followed by transfer of F1 (CAP X LEW) marrow, which is una...

BACKGROUND The combination of cisplatin and etoposide is effective in the treatment of small cell lung carcinomas and other high-grade neuroendocrine tumors (NET). This combination has been considered as a default treatment for patients with high-grade NET of the colon and rectum (CRC). No formal series has yet described the activity of this regimen in this patient population. A retrospective s...

Because topoisomerase (topo) I- and topo II-targeting agents exert their principal effects on the two major classes of enzymes involved in regulating DNA topology in the cell, there has been considerable interest in evaluating combinations of these classes of agents. In preclinical studies of inhibitors of topo I and topo II in combination, drug scheduling and sequencing have been critical dete...

The purpose of this study was to prospectively test a pharmacodynamic model for therapeutic drug monitoring of 21-day oral etoposide. In our previous studies, etoposide trough concentrations on this schedule were related to the hematological toxicity, expressed as WBC and neutrophil counts at the nadir. The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (AN...

Topoisomerase II is a target for clinically active anticancer drugs. Drugs targeting these enzymes act by preventing the religation of enzyme-DNA covalent complexes leading to protein-DNA adducts that include single- and double-strand breaks. In mammalian cells, nonhomologous repair pathways are critical for repairing topoisomerase II-mediated DNA damage. Because topoisomerase II-targeting agen...

PURPOSE To investigate pharmacologically guided addition of etoposide to a weekly irinotecan/cisplatin chemotherapy. PATIENTS AND METHODS Patients with advanced nonhematologic malignancies were eligible. Treatment consisted of i.v. administration of 50 mg/m(2) irinotecan and 20 mg/m(2) cisplatin on days 1, 8, 15, and 22 of a 42-day cycle or on days 1 and 8 of a 21-day cycle. Etoposide was adm...