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Preclinical Development of New Alkylating Oligopeptides for Cancer Therapy

Gullbo, Joachim, 1971- (författare)
Uppsala universitet,Klinisk farmakologi
Larsson, Rolf (preses)
Nygren, Peter (preses)
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Eriksson, Staffan, Professor (opponent)
Molekylär Biovetenskap SLU, Uppsala
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 (creator_code:org_t)
ISBN 9155458114
Uppsala : Acta Universitatis Upsaliensis, 2003
Engelska 59 s.
Serie: Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1308
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

Nyckelord

Pharmacology
pharmacology
oncology
chemistry
Melphalan derivatives
Farmakologi
Pharmacological research
Farmakologisk forskning

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vet (ämneskategori)
dok (ämneskategori)

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