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Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2003 (English)In: Oncology Research, ISSN 0965-0407, Vol. 14, no 3, 113-132 p.Article in journal (Refereed) Published
Abstract [en]

The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.

Place, publisher, year, edition, pages
2003. Vol. 14, no 3, 113-132 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91098PubMedID: 14760861OAI: oai:DiVA.org:uu-91098DiVA: diva2:163695
Available from: 2003-11-19 Created: 2003-11-19 Last updated: 2013-07-03Bibliographically approved
In thesis
1. Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy
Open this publication in new window or tab >>Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oligopeptides can be used to carry cytotoxic agents in cancer chemotherapy, using tumour-associated proteins as the molecular target for selectivity. During the seventies and eighties Peptichemio, a cocktail of six alkylating oligopeptides carrying m-L-sarcolysin, was investigated in a wide variety of human malignancies. Positive clinical results were suggested to result from rapid and effective DNA-crosslinking following uptake in neoplastic cells, but also from antimetabolic properties of the drug. Although m-L-sarcolysin never reached widespread clinical use, the well established para-isomer melphalan still, after nearly fifty years, has a place in cancer chemotherapy.

The present study was undertaken to synthesise the melphalan containing analogue of the tripeptide P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester, the main contributor to Peptichemio’s activity) and similar compounds, preferably dipeptides. The new compounds compared favourably with melphalan, m-L-sarcolysin and P2, considering their potency in vitro. Structure activity relationship analysis showed that the activity of melphalan dipeptides depended on the amino acid composition, sequence and end group modifications, but only to a minor degree on lipophilicity. Results suggested that the dipeptides, to exert their full cytotoxic activity, had to interact with specific biomolecules such as dipeptide transporters or peptidases. Although no active transport could be demonstrated the influence of peptide hydrolysis was obvious, thereby suggesting a rationale for increased activity as well as potential tumour selectivity in comparison with melphalan.

Preliminary in vivo studies in mice supported the results, despite equal alkylating capacity the dipeptide J1 (melphalanyl-p-L-fluorophenylalanine ethyl ester) and the tripeptide J3 (L-prolyl-melphalanyl-p-L-fluorophenylalanine ethyl ester) were more active than was melphalan on human tumour cells implanted in test animals although all drugs produced expected side effects, notably leukopenia, of similar magnitude.

In conclusion, oligopeptide derivatives of melphalan seem to provide improved cytotoxic activity and therapeutic index. Further development of such oligopeptides for clinical use seems worthwhile.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 59 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1308
Pharmacology, pharmacology, oncology, chemistry, Melphalan derivatives, Farmakologi
National Category
Pharmacology and Toxicology
urn:nbn:se:uu:diva-3785 (URN)91-554-5811-4 (ISBN)
Public defence
2003-12-12, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15
Available from: 2003-11-19 Created: 2003-11-19Bibliographically approved

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Gullbo, JoachimNygren, PeterLarsson, Rolf
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