Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester): comparison with melphalan
作者:
Joachim Gullbo,
Sumeer Dhar,
Kristina Luthman,
Hans Ehrsson,
Rolf Lewensohn,
Peter Nygren,
Rolf Larsson,
期刊:
Anti-Cancer Drugs
(OVID Available online 2003)
卷期:
Volume 14,
issue 8
页码: 617-624
ISSN:0959-4973
年代: 2003
出版商: OVID
关键词: alkylating peptides;cytotoxicity;melphalan;P2;peptichemio
数据来源: OVID
摘要:
Peptichemio, a mixture of six short oligopeptides all comprising the alkylating amino acidm-L-sarcolysin, has shown clinical activity in several malignancies. Previous studies have suggested that activity mainly resides in one of the peptides, P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester). In the present study thein vitroactivity of P2 was further investigated and compared to melphalan and the novel alkylating dipeptide J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), which is structurally related to P2 and melphalan. Cytotoxic activity was studied using patient tumor cells in a non-clonogenic cytotoxicity assay, whereas cellular response, and kinetics thereof, were studied in the lymphoma cell line U-937 GTB. Cellular metabolism was studied using microphysiometry, kinetic effects on macromolecular synthesis by radiolabeled substrate incorporation and, finally, the microculture kinetic assay of apoptosis was used to monitor morphologic changes following drug exposure. The assays compared P2 favorably with melphalan. Interestingly J1 was even more cytotoxic, and produced more pronounced effects in the kinetic assays for macromolecular synthesis, metabolic activity and apoptosis. The results indicate that the delivery properties of J1 are improved compared to those of melphalan and P2.
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