In vitro synergism of 4-hydroperoxycyclophosphamide and cisplatin: relevance for bone marrow purging |
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| Authors: | Richard H. Peters Carlene S. Brandon Lobelia A. Avila O. Michael Colvin Robert K. Stuart |
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| Affiliation: | (1) Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA;(2) Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA;(3) The Johns Hopkins Oncology Center, Baltimore, Maryland, USA;(4) Hematology/Oncology Division, Department of Medicine, Medical University of South Carolina, 171 Ashley Avenue, 29425 Charleston, SC, USA |
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| Abstract: | Summary Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide (4-HC)-purged bone marrow gives long-term remission in almost half of relapsed acute nonlymphocytic leukemia and non-Hodgkin's lymphoma patients, but relapse of disease is the main cause of failure, suggesting ineffective purging in some cases. Cisplatin (CP) has activity against a variety of human tumors and is not commonly used for initial therapy of leukemia and lymphoma. Using established human leukemia cell lines, combinations of 4-HC and CP were investigated as a potential regimen for improving the ex vivo removal of leukemia cells from bone marrow. The cell lines (K-562 and Raji) were incubated for 1 (4-HC) or 4 h (CP), washed, and assayed for inhibition of colony formation in semisolid media. In both cell lines, CP (4 h) was more potent than 4-HC (1 h). Combinations of the drugs in various molar ratios were studied after the cells were sequentially incubated with 4-HC and CP. The effects of the drugs were analyzed using the multiple drug-effect analysis of Chou and Talalay [6]. Analysis of data on in vitro inhibition of colony formation suggested that all combinations studied were synergistic in both cell lines, with the greatest synergism being found in the Raji cell line. In addition, for K-562 cells we could detect at least a 4.6 log reduction in cloning with the CP:4-HC combination (1:10 molar ratio). We conclude that CP is a potential candidate in drug combinations for ex vivo bone marrow purging because of its high potency against human leukemia cell lines, its synergistic activity in combination with 4-HC, and its ability to reduce a high tumor burden when combined with 4-HC.Supported in part by grants from the Oliver S. and Jennie R. Donaldson Charitable Trust and from the Westvaco Corporation. Portions of this work were presented at the 78th Annual Meeting of the American Association for Cancer Research, Atlanta, Ga, May 20–23, 1987 |
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